Autoimmune disorder treatment using RXR agonists

ABSTRACT

The present specification provides RXR agonist compounds, compositions comprising such RXR agonists, and methods using such compounds and compositions to treat an autoimmune disorder, inflammation associated with an autoimmune disorder and/or a transplant rejection as well as use of such RXR agonists to manufacture a medicament and use of such compounds and compositions to treat an autoimmune disorder, inflammation associated with an autoimmune disorder and/or a transplant rejection.

This patent application is a division of U.S. patent application Ser.No. 17/126,787, filed Dec. 18, 2020, now U.S. Pat. No. 11,246,845, whichis a continuation of U.S. patent application Ser. No. 16/742,616, filedJan. 14, 2020, which is a continuation of U.S. patent application Ser.No. 16/228,217, filed Dec. 20, 2018, now U.S. Pat. No. 10,945,976, whichis a continuation of U.S. patent application Ser. No. 15/852,580, filedDec. 22, 2017, now U.S. Pat. No. 10,201,512 which is a continuation ofU.S. patent application Ser. No. 15/341,969, filed Nov. 2, 2016, nowU.S. Pat. No. 10,285,960, which is a continuation of U.S. patentapplication Ser. No. 13/714,051 filed Dec. 13, 2012, now abandoned,which claims priority pursuant to 35 U.S.C. § 119(e) to U.S. ProvisionalPatent Application Ser. No. 61/570,182, filed Dec. 13, 2011, each ofwhich is hereby incorporated by reference in its entirety.

This invention was made with government support under R01-CA062275 andR01-AT005382 awarded by National Institutes of Health (NIH). Thegovernment has certain rights in the invention.

Attempts to treat autoimmune disorders have met with limited success.This is due, in part, to the fact that the etiology of autoimmunedisorders is a complex response based in part on a combination offactors, including, without limitation, genetic make-up of individual,gender or hormonal status, bacterial or viral infection, metal orchemical toxin exposure, vaccinations or immunizations, stress, trauma,smoking and/or nutritional deficiencies. Therefore, compounds,compositions, and methods that can reduce a symptom associated with anautoimmune disorder, inflammation associated with an autoimmunedisorder, and/or a transplant rejection would be highly desirable.

Naïve CD4⁺ T cells play a central role in immune protection. They do sothrough their capacity to help B cells make antibodies, to inducemacrophages to develop enhanced microbicidal activity, to recruitneutrophils, eosinophils, and basophils to sites of infection andinflammation, and, through their production of cytokines and chemokines,to orchestrate the full panoply of immune responses. Naïve CD4⁺ T cellsare multipotential precursors that differentiate into various T cellsubsets, such as, e.g., T helper (Th) cells (also called T effectorcells) and T regulatory (Treg) cells. T helper cells are characterizedby their distinct functions and include Th1, Th2, and Th17. Th1 cellsaid in the clearance of intracellular bacteria and viruses, secreteIFN-γ in response to the cytokine interleukin-12 (IL-12), and requirethe transcription factors T-box21 (T-bet) and signal transducer andactivator of transcription 1 (Stat1) and (Stat4). Th2 cells help controlextracellular pathogens, secrete the cytokines IL-4, IL-5 and IL-13, andrequire transcription factors GATA-binding protein 3 (GATA-3) and Stat6.Th17 cells provide protection against fungi and various otherextracellular bacteria, secrete the pro-inflammatory cytokine IL-17A,and express the transcription factor retinoic acid orphan receptor gamma(RORγt). Treg cells play a critical role in maintaining self-toleranceas well as in regulating immune responses and express the transcriptionfactor forkhead box P3 (FoxP3). Tregs normally develop in the thymus,but can also differentiate from naïve CD4⁺ cells stimulated with TGF-βand IL-2. Development and differentiation of Treg cells, as well asexpression of FoxP3, require the transcription factor Stat5.

Although several cytokines participate in Th17 cell differentiation,IL-6 and TGF-β are key factors for the generation of Th17 cells fromnaïve T CD4⁺ cells. On the other hand, IL-6 inhibits TGF-β-induced Tregcells which suppress adaptive T cell responses and prevent autoimmunity,and are thus important in the maintenance of immune homeostasis. The twoT-cell subsets play prominent roles in immune functions: Th17 plays akey role in the pathogenesis of autoimmune diseases and protectionagainst bacterial infections, while Treg functions to restrain excessivehelper T-cell responses. Essentially immunosuppressive Tregs cells andpro-inflammatory Th17 cells functionally antagonize each other.

As such, a fine balance between Th17 and Treg cells may be crucial forthe stability of immune homeostasis. Once the equilibrium is broken, thedestabilization may lead to chronic inflammation and autoimmunity. Forexample, dysregulation or overproduction of IL-6 leads to autoimmunediseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA),in which Th17 cells are considered to be the primary cause of pathology.Clinical evidence indicates that both defects in Treg function orreduced numbers, as well as Th17 activity are important in severalautoimmune diseases, including seronegative arthritis in adults, andchildhood arthritis (juvenile idiopathic arthritis). Therefore, aneffective approach in the treatment of various autoimmune andinflammatory diseases will be to normalize the balance between Treg andTh17 cell development.

There are two main types of receptors that mediate the effects ofderivatives of vitamin A in mammals (and other organisms), the RetinoicAcid Receptors (RARs) and the Retinoid X Receptors (RXRs). Within eachtype there are three subtypes designated RAR alpha, RAR beta, and RARgamma for the RAR family and RXR alpha, RXR beta, and RXR gamma for theRXR family. These receptor types are evolutionarily related but arefunctionally distinct. The ligands that activate the RARs, referred toas retinoids, and the ligands that activate the RXRs, referred to asrexinoids, elicit quite different biological effects. Retinoic acid(RA), the physiological hormone of all three RARs, has been shown toenhance the in vitro differentiation of Treg cells that suppressimmunity. RA can also inhibit the differentiation of pro-inflammatoryTh17 cells that have been casually implicated in the development of manyhuman autoimmune diseases. Based on this ability to restore a normalTh17/Treg cell ratio by decreasing Th17 cells while simultaneouslyincreasing Treg cells, RAR agonists have been proposed as effectivetherapeutic compounds for the treatment of inflammatory and autoimmunedisorders. However, recent findings have identified retinoid signalingthrough RARs as being required for the initial development of Th17 cellmediated immune responses and inflammation. These counteracting effectsof RAR pan agonists on Th17 cell development bring into question thevalue of such compounds as anti-inflammatory and immunosuppressiveagents.

Although RAR agonists like RA have been used to treat autoimmunedisorders associated with inflammation, their usefulness in clinicalpractice has been limited due to unwanted side effects andcounter-therapeutic inflammatory effects. Thus, what are needed arecompounds and compositions that maintain the ability to inhibit Th17cell formation and function and to promote Treg cell formation, but notpossess any pro-inflammatory activities and other unwanted side effectsassociated with RAR pan agonists like RA. Such compounds will be ofconsiderable therapeutic value as immunomodulatory agents.

The present specification discloses compounds, compositions, and methodsfor treating an individual suffering from an autoimmune disorder. Thisis accomplished by administering a therapeutically effective amount of aRXR agonist or composition comprising such agonist to an individualsuffering from an autoimmune disorder. As disclosed herein, thedisclosed RXR agonists can control the Th17/Treg cell number ratio byelevating Treg cell numbers and suppressing Th17 cell numbers. As such,the disclosed RXR agonists would be useful in treating an autoimmunedisorder.

SUMMARY

Thus, aspects of the present specification disclose a RXR agonist.Non-limiting examples of a RXR agonist include a compound having thestructure of formula I,

wherein Z is a radical having the structure of Formula II:

Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substitutedwith one or two R⁴ groups, or Y is selected from phenyl, pyridyl,thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl,oxazolyl, and imidazolyl, the groups being optionally substituted withone or two R⁴ groups, the divalent Y radical being substituted by the Zand —(CR¹═CR¹=CR¹═CR¹)— groups on adjacent carbons; R¹ and R²independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen, loweralkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or halogen, and B ishydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR⁸,—CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O,—OCOR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or tri-lower alkylsilyl, where R⁷ is analkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons, R⁸ is analkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R⁸ isphenyl or lower alkylphenyl, R⁹ and R¹⁰ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or loweralkylphenyl, R¹² is lower alkyl, R¹³ is divalent alkyl radical of 2-5carbons; and n is 1 or 2.

Other aspects of the present specification disclose a method of treatingan autoimmune disorder, the method comprising the step of administeringto an individual in need thereof a therapeutically effective amount of aRXR agonist, wherein administration of the compound or compositionreduces a symptom associated with the autoimmune disorder, therebytreating the individual. Aspects of the present specification alsodisclose a use of a RXR agonist to treat an autoimmune disorder, whereinadministration of the compound or composition reduces a symptomassociated with the autoimmune disorder, thereby treating theindividual. Non-limiting examples of a RXR agonist include a compound ora composition disclosed herein. The autoimmune disorder can be asystemic autoimmune disorder or an organ-specific autoimmune disorder.Non-limiting examples of an autoimmune disorder that can be treatedusing a compound or a composition disclosed herein include an acutedisseminated encephalomyelitis (ADEM), an Addison's disease, an allergy,allergic rhinitis, an Alzheimer's disease, an anti-phospholipid antibodysyndrome (APS), an arthritis such as, e.g., a monoarthritis, anoligoarthritis, or a polyarthritis like an osteoarthritis, a rheumatoidarthritis, a juvenile idiopathic arthritis, a septic arthritis, aspondyloarthropathy, a gout, a pseudogout, or Still's disease, anasthma, an autoimmune deficiency syndrome (AIDS), an autoimmunehemolytic anemia, an autoimmune hepatitis, an autoimmune inner eardisease, a bullous pemphigoid, a celiac disease, a Chagas disease, achronic obstructive pulmonary disease (COPD), a diabetes mellitus type 1(IDDM), an endometriosis, a gastrointestinal disorder such as, e.g., anirritable bowel disease or an inflammatory bowel disease like Crohn'sdisease or an ulcerative colitis, a Goodpasture's syndrome, a Graves'disease, a Guillain-Barré syndrome (GBS), a Hashimoto's thyroiditis, ahidradenitis suppurativa, an idiopathic thrombocytopenic purpura, aninterstitial cystitis, a lupus, such as, e.g., a discoid lupuserythematosus, a drug-induced lupus erythematosus. a lupus nephritis, aneonatal lupus, a subacute cutaneous lupus erythematosus, or a systemiclupus erythematosus, a morphea, a multiple sclerosis (MS), a myastheniagravis, a myopathy such as, e.g., a dermatomyositis, an inclusion bodymyositis, or a polymyositis, a myositis, a narcolepsy, a neuromyotonia,a Parkinson's disease, a pemphigus vulgaris, a pernicious anaemia, aprimary biliary cirrhosis, a psoriasis, a recurrent disseminatedencephalomyelitis, a rheumatic fever, a schizophrenia, a scleroderma, aSjögren's syndrome, a skin disorder such as, e.g., dermatitis, aneczema, a statis dermatitis, a hidradenitis suppurativa, a psoriasis, arosacea or a scleroderma, a tenosynovitis, a uveitis, vasculitis suchas, e.g., a Buerger's disease, a cerebral vasculitis, a Churg-Straussarteritis, a cryoglobulinemia, an essential cryoglobulinemic vasculitis,a giant cell arteritis, a Golfer's vasculitis, a Henoch-Schonleinpurpura, a hypersensitivity vasculitis, a Kawasaki disease, amicroscopic polyarteritis/polyangiitis, a polyarteritis nodosa, apolymyalgia rheumatica (PMR), a rheumatoid vasculitis, a Takayasuarteritis, or a Wegener's granulomatosis, or a vitiligo. Non-limitingexamples of a symptom reduced by a method of treating an autoimmunedisorder disclosed herein include inflammation, fatigue, dizziness,malaise, elevated fever and high body temperature, extreme sensitivityto cold in the hands and feet, weakness and stiffness in muscles andjoints, weight changes, digestive or gastrointestinal problems, low orhigh blood pressure, irritability, anxiety, or depression, infertilityor reduced sex drive (low libido), blood sugar changes, and depending onthe type of autoimmune disease, an increase in the size of an organ ortissue, or the destruction of an organ or tissue. Non-limiting examplesof an inflammation symptom reduced by a method of treating an autoimmunedisorder disclosed herein include edema, hyperemia, erythema, bruising,tenderness, stiffness, swollenness, fever, a chill, congestion of therespiratory tract including nose, and bronchi, congestion of a sinus, abreathing problem, fluid retention, a blood clot, a loss of appetite, anincreased heart rate, a formation of granulomas, fibrinous, pus, ornon-viscous serous fluid, a formation of an ulcer, or pain.

Yet other aspects of the present specification disclose a method oftreating inflammation as a result of an autoimmune disorder, the methodcomprising the step of administering to an individual in need thereof atherapeutically effective amount of a RXR agonist, whereinadministration of the compound or composition reduces a symptomassociated with inflammation, thereby treating the individual. Aspectsof the present specification also disclose a use of a RXR agonist totreat inflammation as a result of an autoimmune disorder, whereinadministration of the compound or composition reduces a symptomassociated with inflammation, thereby treating the individual.Non-limiting examples of a RXR agonist include a compound or acomposition disclosed herein. Non-limiting examples of a symptom reducedby a method of treating inflammation disclosed herein include edema,hyperemia, erythema, bruising, tenderness, stiffness, swollenness,fever, a chill, congestion of the respiratory tract including nose, andbronchi, congestion of a sinus, a breathing problem, fluid retention, ablood clot, a loss of appetite, an increased heart rate, a formation ofgranulomas, fibrinous, pus, or non-viscous serous fluid, a formation ofan ulcer, or pain.

Still aspects of the present specification disclose a method of treatinga transplant rejection, the method comprising the step of administeringto an individual in need thereof a therapeutically effective amount of aRXR agonist, wherein administration of the RXR agonist reduces a symptomassociated with the transplant rejection, thereby treating theindividual. Aspects of the present specification also disclose a use ofa RXR agonist to treat a transplant rejection, wherein administration ofthe compound or composition reduces a symptom associated with thetransplant rejection, thereby treating the individual. Non-limitingexamples of a RXR agonist include a compound or a composition disclosedherein. Non-limiting examples of a transplant rejection include ahyperacute rejection, an acute rejection, or a chronic rejection, aswell as, a graft-versus-host-disease. Non-limiting examples of a symptomreduced by a method of treating a transplant rejection disclosed hereininclude inflammation, fatigue, dizziness, malaise, elevated fever andhigh body temperature, extreme sensitivity to cold in the hands andfeet, weakness and stiffness in muscles and joints, weight changes,digestive or gastrointestinal problems, low or high blood pressure,irritability, anxiety, or depression, infertility or reduced sex drive(low libido), blood sugar changes, and depending on the type ofautoimmune disease, an increase in the size of an organ or tissue, orthe destruction of an organ or tissue. Non-limiting examples of aninflammation symptom reduced by a method of treating a transplantrejection include edema, hyperemia, erythema, bruising, tenderness,stiffness, swollenness, fever, a chill, congestion of the respiratorytract including nose, and bronchi, congestion of a sinus, a breathingproblem, fluid retention, a blood clot, a loss of appetite, an increasedheart rate, a formation of granulomas, fibrinous, pus, or non-viscousserous fluid, a formation of an ulcer, or pain.

Further aspects of the present specification disclose a method ofpromoting Treg cell differentiation in an individual, the methodcomprising the step of administering to the individual in need thereof atherapeutically effective amount of a RXR agonist, whereinadministration of the RXR agonist promotes Treg cell differentiation.Aspects of the present specification also disclose a use of a RXRagonist to promote Treg cell differentiation in an individual, whereinadministration of the RXR agonist to the individual promotes Treg celldifferentiation. Administration of the RXR agonist to the individual canalso inhibit Th17 cell differentiation.

Further aspects of the present specification disclose a method ofinhibiting Th17 cell differentiation in an individual, the methodcomprising the step of administering to the individual in need thereof atherapeutically effective amount of a RXR agonist, whereinadministration of the RXR agonist inhibits Th17 cell differentiation.Aspects of the present specification also disclose a use of a RXRagonist to inhibit Th17 cell differentiation in an individual, whereinadministration of the RXR agonist to the individual inhibits Th17 celldifferentiation. Administration of the RXR agonist to the individual canalso promote Treg cell differentiation.

Other aspects of the present specification disclose a method ofconcurrently promoting Treg cell differentiation as well as inhibitingTh17 cell differentiation in an individual, the method comprising thestep of administering to the individual in need thereof atherapeutically effective amount of a RXR agonist, whereinadministration of the RXR agonist promotes Treg cell differentiation andinhibits Th17 cell differentiation. Aspects of the present specificationalso disclose a use of a RXR agonist to concurrently promote Treg celldifferentiation as well as inhibit Th17 cell differentiation in anindividual, wherein administration of the RXR agonist to the individualpromotes Treg cell differentiation and inhibits Th17 celldifferentiation.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A-B shows RXR agonist effects on gene expression. FIG. 1A showsthat RXR agonists regulate Foxp3 expression and FIG. 1B shows that RXRagonists regulate and α4β7 expression.

FIG. 2A-B shows RXR agonist effects on differentiation. FIG. 2A showsthat RXR agonists increase Treg differentiation under Th17 conditionsand FIG. 2B shows that RXR agonists inhibit Th17 differentiation underTh17 conditions (B).

FIG. 3 shows the effects of RAR signaling inhibition on RXR agonistinducement of Treg differentiation.

FIG. 4 shows RXR agonist activation of transcription from RXRα, RXRβ,RXRγ, RARα, RARβ, and RARγ using transactivation assays.

FIG. 5 shows that RXR agonists attenuate experimental autoimmuneencephalomyelitis (EAE) in C57BL/6 mice.

FIG. 6A-B shows that RXR agonists reduce leukocyte infiltration into thecentral nervous system. FIG. 6A shows that RXR agonists reduce CD4+ Tcell infiltration into the central nervous system; and FIG. 6B showsthat RXR agonists reduce myeloid dendritic cell infiltration into thecentral nervous system.

FIG. 7 shows RXR agonists attenuate EAE in SJL mice.

DESCRIPTION

The RARs and RXRs and their cognate ligands function by distinctmechanisms. The RARs always form heterodimers with RXRs and theseRAR/RXR heterodimers bind to specific response elements in the promoterregions of target genes. The binding of RAR agonists to the RAR receptorof the heterodimer results in activation of transcription of targetgenes leading to retinoid effects. On the other hand, RXR agonists donot activate RAR/RXR heterodimers. RXR heterodimer complexes likeRAR/RXR, can be referred to as non-permissive RXR heterodimers asactivation of transcription due to ligand-binding occurs only at thenon-RXR protein (e.g., RAR); activation of transcription due to ligandbinding does not occur at the RXR. RXRs also interact with nuclearreceptors other than RARs and RXR agonists may elicit some of itsbiological effects by binding to such RXR/receptor complexes. TheseRXR/receptor complexes can be referred to as permissive RXR heterodimersas activation of transcription due to ligand-binding could occur at theRXR, the other receptor, or both receptors. Examples of RXR permissiveheterodimers include, without limitation, peroxisome proliferatoractivated receptor/RXR (PPAR/RXR), farnesyl X receptor/RXR (FXR/RXR), orliver X receptor/RXR (LXR/RXR). Alternately, RXRs may form RXR/RXRhomodimers which can be activated by RXR agonists leading to rexinoideffects. Also, RXRs interact with proteins other than nuclear receptorsand ligand binding to an RXR within such protein complexes can also leadto rexinoid effects. Due to these differences in mechanisms of action,RXR agonists and RAR agonists elicit distinct biological outcomes andeven in the instances where they mediate similar biological effects,they do so by different mechanisms. Moreover, the unwanted side effectsof retinoids, such as pro-inflammatory responses or mucocutaneoustoxicity, are mediated by activation of one or more of the RAR receptorsubtypes. Stated another way, biological effects mediated via RXRpathways would not induce pro-inflammatory responses, and thus, wouldnot result in unwanted side effects.

As disclosed herein, RXR agonists inhibit Th17 cell formation andpromote Treg cell formation by mechanisms that do not involve theirfunction as RAR agonists. As such, a selective RXR agonist that does notactivate RARs would be a more effective agent in the treatment of anautoimmune disorder, inflammation associated with an autoimmunedisorder, or a transplant rejection. In support of this, the presentspecification discloses that RXR agonists have cell differentiatingeffects in that they can regulate the Th17/Treg cell number ratio byelevating Treg cell numbers and suppressing Th17 cell numbers. In thismanner, a normal balance of both these cell types can be achieved andimmune homeostatis restored. Furthermore, since selective RXR agonistsachieve these therapeutic effects without activation of RARs, they wouldbe optimally effective and beneficial in treating an autoimmunedisorder, inflammation associated with an autoimmune disorder, or atransplant rejection.

Thus, aspects of the present specification provide, in part, a RXRagonist. As used herein, the term “RXR agonist”, is synonymous with “RXRselective agonist” and refers to a compound that selectively binds toone or more RXR receptors like a RXRα, a RXRβ, or a RXRγ in a mannerthat elicits gene transcription via an RXR response element. As usedherein, the term “selectively binds,” when made in reference to a RXRagonist, refers to the discriminatory binding of a RXR agonist to theindicated target receptor like a RXRα, a RXRβ, or a RXRγ such that theRXR agonist does not substantially bind with non-target receptors like aRARα, a RARβ or a RARγ.

A RXR agonist may be a pure RXR agonist. A pure RXR agonist is one whichdoes not activate to any appreciable degree a permissive heterodimersuch as, e.g., PPAR/RXR, FXR/RXR, and LXR/RXR. One example of a pure RXRagonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid (RXR agonist 194204) disclosed herein, the structureof which is shown in Formula XXIX. In an aspect of this embodiment, apure RXR agonist shows no ability to activate a permissive heterodimer.In another aspect of this embodiment, a pure RXR agonist shows noability to activate PPAR/RXR, FXR/RXR, and/or LXR/RXR. In other aspectsof this embodiment, a pure RXR agonist activates a permissiveheterodimer by 1% or less, 2% or less, 3% or less, 4% or less, 5% orless, 6% or less, 7% or less, 8% or less, 9% or less, or 10% or lessrelative to the ability of a non-pure RXR agonist to activate the samepermissive heterodimer. A non-pure RXR agonist is one that can activatea permissive heterodimer like PPAR/RXR, FXR/RXR, or LXR/RXR. Example ofa non-pure RXR agonist include, e.g., LGD1069 (bexarotene) and LGD268.

Selective binding of a RXR agonist to a RXR receptor includes bindingproperties such as, e.g., binding affinity and binding specificity.Binding affinity refers to the length of time a RXR agonist resides atits RXR receptor binding site, and can be viewed as the strength withwhich a RXR agonist binds its a RXR receptor. Binding affinity can bedescribed as a RXR agonist's equilibrium dissociation constant (KD),which is defined as the ratio Kd/Ka at equilibrium, where Ka is a RXRagonist's association rate constant and kd is a RXR agonist'sdissociation rate constant. Binding affinity is determined by both theassociation and the dissociation and alone neither high association norlow dissociation can ensure high affinity. The association rate constant(Ka), or on-rate constant (Kon), measures the number of binding eventsper unit time, or the propensity of a RXR agonist and its RXR receptorto associate reversibly into its agonist-receptor complex. Theassociation rate constant is expressed in M⁻¹ s⁻¹, and is symbolized asfollows: [Ag]×[Rc]×Kon. The larger the association rate constant, themore rapidly a RXR agonist binds to its RXR receptor, or the higher thebinding affinity between agonist and receptor. The dissociation rateconstant (Kd), or off-rate constant (Koff), measures the number ofdissociation events per unit time propensity of an agonist-receptorcomplex to separate (dissociate) reversibly into its componentmolecules, namely the RXR agonist and the RXR receptor. The dissociationrate constant is expressed in s⁻¹, and is symbolized as follows:[Ag+Rc]×Koff. The smaller the dissociation rate constant, the moretightly bound a RXR agonist is to its RXR receptor, or the higher thebinding affinity between agonist and receptor. The equilibriumdissociation constant (KD) measures the rate at which newagonist-receptor complexes formed equals the rate at whichagonist-receptor complexes dissociate at equilibrium. The equilibriumdissociation constant is expressed in M, and is defined asKoff/Kon=[Ag]×[Rc]/[Ag+Rc], where [Ag] is the molar concentration of aRXR agonist, [Rc] is the molar concentration of the RXR receptor, and[Ag+Rc] is the of molar concentration of the agonist-receptor complex,where all concentrations are of such components when the system is atequilibrium. The smaller the equilibrium dissociation constant, the moretightly bound a RXR agonist is to its RXR receptor, or the higher thebinding affinity between agonist and receptor.

In aspects of this embodiment, the binding affinity of a RXR agonistthat selectively binds to a RXR receptor can have an association rateconstant of, e.g., less than 1×10⁵ M⁻¹ s⁻¹, less than 1×10⁶ M⁻¹ s⁻¹,less than 1×10⁷ M⁻¹ s⁻¹, or less than 1×10⁸ M⁻¹ s⁻¹. In anotherembodiment, the binding affinity of a RXR agonist that selectively bindsto a RXR receptor can have an association rate constant of, e.g., morethan 1×10⁵ M⁻¹ s⁻¹, more than 1×10⁶ M⁻¹ s⁻¹, more than 1×10⁷ M⁻¹ s⁻¹, ormore than 1×10⁸ M⁻¹ s⁻¹. In other aspects, the binding affinity of a RXRagonist that selectively binds to a RXR receptor can have an associationrate constant between, e.g., 1×10⁵ M⁻¹ s⁻¹ to 1×10⁸ M⁻¹ s⁻¹, 1×10⁶ M⁻¹s⁻¹ to 1×10⁸ M⁻¹ s⁻¹, 1×10⁵ M⁻¹ s⁻¹ to 1×10⁷ M⁻¹ s⁻¹, or 1×10⁶ M⁻¹ s⁻¹to 1×10⁷ M⁻¹ s⁻¹.

In other aspects of this embodiment, the binding affinity of a RXRagonist that selectively binds to a RXR receptor can have adisassociation rate constant of, e.g., less than 1×10⁻³ s⁻¹, less than1×10⁻⁴ s⁻¹, or less than 1×10⁻⁵ s⁻¹. In another embodiment, the bindingaffinity of a RXR agonist that selectively binds to a RXR receptor canhave a disassociation rate constant of, e.g., more than 1×10⁻³ s⁻¹, morethan 1×10⁻⁴ s⁻¹, or more than 1×10⁻⁵ s⁻¹. In other aspects, the bindingaffinity of a RXR agonist that selectively binds to a RXR receptor canhave a disassociation rate constant between, e.g., 1×10⁻³ s⁻¹ to 1×10⁻⁵s⁻¹, 1×10⁻³ s⁻¹ to 1×10⁻⁴ s⁻¹, or 1×10⁻⁴ s⁻¹ to 1×10⁻⁵ s⁻¹.

In yet other aspects of this embodiment, the binding affinity of a RXRagonist that selectively binds to a RXR receptor can have an equilibriumdisassociation constant of less than 100 nM. In aspects of thisembodiment, the binding affinity of a RXR agonist that selectively bindsto a RXR receptor can have an equilibrium disassociation constant of,e.g., less than 100 nM, less than 90 nM, less than 80 nM, less than 70nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM,less than 20 nM, or less than 10 nM. In aspects of this embodiment, thebinding affinity of a RXR agonist that selectively binds to a RXRreceptor can have an equilibrium disassociation between, e.g., 0.1 nM to10 nM, 0.1 nM to 50 nM, 0.1 nM to 100 nM, 0.5 nM to 10 nM, 0.5 nM to 50nM, 0.5 nM to 100 nM, 1 nM to 10 nM, 1 nM to 50 nM, or 1 nM to 100 nM.

In still other aspects of this embodiment, the binding affinity of a RXRagonist that selectively binds to a RXR can have an association rateconstant for a RAR receptor of, e.g., less than 1×10⁰ M⁻¹ s⁻¹, less than1×10¹ M⁻¹ s⁻¹, less than 1×10² M⁻¹ s⁻¹, less than 1×10³ M⁻¹ s⁻¹, or lessthan 1×10⁴ M⁻¹ s⁻¹. In another embodiment, the binding affinity of a RXRagonist that selectively binds to a RXR receptor can have an associationrate constant of a RAR receptor of, e.g., at most 1×10⁰ M⁻¹ s⁻¹, at most1×10¹ M⁻¹ s⁻¹, at most 1×10² M⁻¹ s⁻¹, at most 1×10³ M⁻¹ s⁻¹, or at most1×10⁴ M⁻¹ s⁻¹.

In further aspects of this embodiment, the binding affinity of a RXRagonist that selectively binds to a RXR receptor can have an equilibriumdisassociation constant for a RAR receptor of, e.g., more than 500 nM,for than 1,000 nM, more than 5,000 nm, or more than 10,000 nM. Inanother embodiment, the binding affinity of a RXR agonist thatselectively binds to a RXR receptor can have an equilibriumdisassociation constant for a RAR receptor between, e.g., 500 nM to10,000 nM, 1,000 nM to 10,000 nM, or 5,000 nM to 10,000 nM.

Binding specificity is the ability of a RXR agonist to discriminatebetween a RXR receptor and a receptor that does not contain its bindingsite, such as, e.g., a RAR receptor. One way to measure bindingspecificity is to compare the Kon association rate of a RXR agonist forits RXR relative to the Kon association rate of a RXR agonist for areceptor that does not contain its binding site. For example, comparingthe association rate constant (Ka) of a RXR agonist for its RXR receptorrelative to a RAR receptor

In aspects of this embodiment, a RXR agonist that selectively binds to aRXR receptor can have an association rate constant (Ka) for a receptornot comprising its binding site of, e.g., less than 1×10⁰ M⁻¹ s⁻¹, lessthan 1×10¹ M⁻¹ s⁻¹, less than 1×10² M⁻¹ s⁻¹, less than 1×10³ M⁻¹ s⁻¹ orless than 1×10⁴ M⁻¹ s⁻¹. In other aspects of this embodiment, a RXRagonist that selectively binds to a RXR receptor can have an associationrate constant (Ka) for a receptor not comprising its binding site of,e.g., at most 1×10⁰ M⁻¹ s⁻¹, at most 1×10¹ M⁻¹ s⁻¹, at most 1×10² M⁻¹s⁻¹, at most 1×10³ M⁻¹ s⁻¹ or at most 1×10⁴ M⁻¹ s⁻¹.

In other aspects of this embodiment, a RXR agonist that selectivelybinds to a RXR receptor can have an association rate constant (Ka) for areceptor not comprising its binding site of, e.g., at least 2-fold more,at least 3-fold more, at least 4-fold more, at least 5-fold more, atleast 6-fold more, at least 7-fold more, at least 8-fold more, or atleast 9-fold more. In further aspects of this embodiment, a RXR agonistthat selectively binds to a RXR receptor can have an association rateconstant (Ka) for a receptor not comprising its binding site of, e.g.,at least 10-fold more, at least 100-fold more, at least 1,000-fold moreor at least 10,000-fold more. In yet other aspects of this embodiment, aRXR agonist that selectively binds to a RXR receptor can have anassociation rate constant (Ka) for a receptor not comprising its bindingsite of, e.g., at most 1-fold more, at most 2-fold more, at most 3-foldmore, at most 4-fold more, at most 5-fold more, at most 6-fold more, atmost 7-fold more, at most 8-fold more, or at most 9-fold more. In yetother aspects of this embodiment, a RXR agonist that selectively bindsto a RXR receptor can have an association rate constant (Ka) for areceptor not comprising its binding site of, e.g., at most 10-fold more,at most 100-fold more, at most 1,000-fold more or at most 10,000-foldmore.

The binding specificity of a RXR agonist that selectively binds to a RXRreceptor can also be characterized as a binding ratio that such a RXRagonist can discriminate its RXR receptor relative to a receptor notcomprising its binding site, such as, e.g., a RAR receptor. In aspectsof this embodiment, a RXR agonist that selectively binds to a RXRreceptor has a binding ratio for its RXR receptor relative to a receptornot comprising its binding site of, e.g., at least 2:1, at least 3:1, atleast 4:1, at least 5:1, at least 64:1, at least 7:1, at least 8:1, atleast 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1,at least 30:1, at least 35:1, or at least 40:1. In other aspects of thisembodiment, a RXR agonist that selectively binds to a RXR receptor has abinding ratio for its RXR receptor relative to a RAR receptor of, e.g.,at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 64:1,at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1,at least 20:1, at least 25:1, at least 30:1, at least 35:1, or at least40:1.

In aspects of this embodiment, a RXR agonist will have a ratio ofactivity at a RXR receptor relative to a RAR receptor of, e.g., at least5 greater, at least 10 greater, at least 15, or at least 20 greater.

The binding specificity of a RXR agonist that selectively binds to a RXRreceptor can also be characterized as an activity ratio that such a RXRagonist can exert activity through binding to its RXR receptor relativeto a receptor not comprising its binding site, such as, e.g., a RARreceptor. In aspects of this embodiment, a RXR agonist that selectivelybinds to a RXR receptor has an activity ratio through its RXR receptorrelative to a receptor not comprising its binding site of, e.g., atleast 2:1, at least 3:1, at least 4:1, at least 5:1, at least 64:1, atleast 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, atleast 20:1, at least 25:1, at least 30:1, at least 35:1, or at least40:1. In other aspects of this embodiment, a RXR agonist thatselectively binds to a RXR receptor has an activity ratio through itsRXR receptor relative to a RAR receptor of, e.g., at least 2:1, at least3:1, at least 4:1, at least 5:1, at least 64:1, at least 7:1, at least8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least25:1, at least 30:1, at least 35:1, or at least 40:1.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula I:

wherein Z is a radical having the structure of Formula II:

Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substitutedwith one or two R⁴ groups, or Y is selected from phenyl, pyridyl,thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl,oxazolyl, and imidazolyl, the groups being optionally substituted withone or two R⁴ groups, the divalent Y radical being substituted by the Zand —(CR¹═CR¹=CR¹═CR¹)— groups on adjacent carbons; R¹ and R²independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen, loweralkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or halogen, and B ishydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR⁸,—CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O,—OCOR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or tri-lower alkylsilyl, where R⁷ is analkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons, R⁸ is analkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R⁸ isphenyl or lower alkylphenyl, R⁹ and R¹⁰ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or loweralkylphenyl, R¹² is lower alkyl, R¹³ is divalent alkyl radical of 2-5carbons; and n is 1 or 2.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula III:

wherein R² is hydrogen or lower alkyl; R³ is hydrogen or lower alkyl,and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,—COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂,—CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or tri-lower alkylsilyl, whereR⁷ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons,R⁸ is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10carbons or trimethylsilylalkyl where the alkyl group has 1 to 10carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ is lower alkyl,phenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ is divalentalkyl radical of 2-5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula IV:

wherein n is 1 or 2; R¹ and R² independently are H, lower alkyl orfluoroalkyl; R³ is hydrogen, lower alkyl, Cl or Br; R⁴ is H, loweralkyl, fluoroalkyl or halogen, and B is hydrogen, —COOH or apharmaceutically acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH,—CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂,—CR⁷OR¹³O, or trilower alkylsilyl where R⁷ is an alkyl, cycloalkyl oralkenyl group containing 1 to 5 carbons, R⁸ is an alkyl group of 1 to 10carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ is lower alkyl,phenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ is divalentalkyl radical of 2-5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula V:

where R⁴ is lower alkyl of 1 to 6 carbons; B is —COOH or —COOR⁸ where R⁸is lower alkyl of 1 to 6 carbons, and the configuration about thecyclopropane ring is cis, and the configuration about the double bondsin the pentadienoic acid or ester chain attached to the cyclopropanering is trans in each of the double bonds, or a pharmaceuticallyacceptable salt of the compound.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula VI:

wherein Z is a radical having the structure of Formula VII:

Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substitutedwith one or two R⁴ groups, or Y is selected from phenyl, pyridyl,thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl,oxazolyl, and imidazolyl, the groups being optionally substituted withone or two R⁴ groups, the divalent Y radical being substituted by the Zand —(CR¹═CR¹=CR¹═CR¹)— groups on adjacent carbons; X is S or O; R¹ andR² independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen,lower alkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or halogen, and Bis hydrogen, —COOH or a pharmaceutically acceptable salt thereof,—COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂,—CHOR¹³O, —OCOR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or tri-lower alkylsilyl, whereR⁷ is an alkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons,R⁸ is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10carbons or trimethylsilylalkyl where the alkyl group has 1 to 10carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ is lower alkyl,phenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ is divalentalkyl radical of 2-5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula VIII:

wherein X is S or O; R² is hydrogen or lower alkyl; R³ is hydrogen orlower alkyl, and B is hydrogen, —COOH or a pharmaceutically acceptablesalt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO,—CH(OR¹²)₂, —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or triloweralkylsilyl, where R⁷ is an alkyl, cycloalkyl or alkenyl group containing1 to 5 carbons, R⁸ is an alkyl group of 1 to 10 carbons, a cycloalkylgroup of 5 to 10 carbons or trimethylsilylalkyl where the alkyl grouphas 1 to 10 carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰independently are hydrogen, an alkyl group of 1 to 10 carbons, or acycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ islower alkyl, phenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ isdivalent alkyl radical of 2-5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula IX:

wherein Z is a radical having the structure of Formula X:

Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups beingoptionally substituted with one or two R⁴ groups, the divalent Y radicalbeing substituted by the Z and —(CR¹═CR¹=CR¹═CR¹)— groups on adjacentcarbons; X is NR⁵; n is 1 or 2; R¹ and R² independently are H, loweralkyl or fluoroalkyl; R³ is hydrogen, lower alkyl, Cl or Br; R⁴ is loweralkyl, fluoroalkyl or halogen; R⁵ is H or lower alkyl, and B ishydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR⁸,—CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR⁸, —CHO, —CH(OR¹²)₂, —CHOR¹³O,—COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or trilower alkylsilyl, where R⁷ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R⁸ is analkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R⁸ isphenyl or lower alkylphenyl, R⁹ and R¹⁰ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or loweralkylphenyl, R¹² is lower alkyl, and R¹³ is divalent alkyl radical of 2to 5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula IX:

wherein Z is a radical having the structure of Formula X:

Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups beingoptionally substituted with one or two R⁴ groups, the divalent Y radicalbeing substituted by the Z and —(CR¹═CR¹=CR¹═CR¹)— groups on adjacentcarbons; X is NR⁵; n is 1 or 2; R¹ and R² independently are H, loweralkyl or fluoroalkyl; R³ is hydrogen, lower alkyl, Cl or Br; R⁴ is loweralkyl, fluoroalkyl or halogen; R⁵ is H or lower alkyl, and B ishydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR⁸,—CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O,—COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or trilower alkylsilyl, where R⁷ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R⁸ is analkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R⁸ isphenyl or lower alkylphenyl, R⁹ and R¹⁰ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or loweralkylphenyl, R¹² is lower alkyl, and R¹³ is divalent alkyl radical of 2to 5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XII:

wherein R is H, lower alkyl or 1 to 6 carbons, or a pharmaceuticallyacceptable salt of the compound.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XII:

wherein Z is a radical having the structure of Formula XIV:

Y is cyclopropyl, the Y group being optionally substituted with one ortwo R⁴ groups, the divalent Y radical being substituted by the Z and—(CR¹═CR¹=CR¹═CR¹)— groups on adjacent carbons; X is NR⁵; R¹ and R²independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen, loweralkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or hydrogen; R⁵ is H orlower alkyl, and B is hydrogen, —COOH or a pharmaceutically acceptablesalt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO,—CH(OR¹²)₂, —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or triloweralkylsilyl, where R⁷ is an alkyl, cycloalkyl or alkenyl group containing1 to 5 carbons, R⁸ is an alkyl group of 1 to 10 carbons, a cycloalkylgroup of 5 to 10 carbons or trimethylsilylalkyl where the alkyl grouphas 1 to 10 carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰independently are hydrogen, an alkyl group of 1 to 10 carbons, or acycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ islower alkyl, phenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ isdivalent alkyl radical of 2 to 5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XV:

wherein X is NR⁵; R⁵ is H or lower alkyl; R² is H or lower alkyl; R³ isH or lower alkyl, and B is hydrogen, —COOH or a pharmaceuticallyacceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹, —CH₂OCOR¹¹,—CHO, —CH(OR¹²)₂, —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or triloweralkylsilyl, where R⁷ is an alkyl, cycloalkyl or alkenyl group containing1 to 5 carbons, R⁸ is an alkyl group of 1 to 10 carbons, a cycloalkylgroup of 5 to 10 carbons or trimethylsilylalkyl where the alkyl grouphas 1 to 10 carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰independently are hydrogen, an alkyl group of 1 to 10 carbons, or acycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ islower alkyl, phenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ isdivalent alkyl radical of 2 to 5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XVI:

where Y is a bivalent radical having the structure of Formula XVII:

the two X¹ groups jointly represent an oxo (═O) or thione (═S) function,or X¹ is independently selected from H or alkyl of 1 to 6 carbons; thetwo X² groups jointly represent an oxo (═O) or a thione (═S) function,or X² independently selected from H or alkyl of 1 to 6 carbons, with theproviso that one of the joint X¹ grouping or of the joint X² groupingrepresents an oxo (═O) or thione (═S) function; W is O, C(R¹)₂, or Wdoes not exist; R¹ is independently H, lower alkyl of 1 to 6 carbons, orlower fluoroalkyl of 1 to 6 carbons; R² is independently H, lower alkylof 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R³ ishydrogen, lower alkyl of 1 to 6 carbons, OR¹, fluoro substituted loweralkyl of 1 to 6 carbons halogen, NO₂, NH₂, —NHCO(C₁-C₆) alkyl, or—NHCO(C₁-C₆) alkenyl; A is hydrogen, —COOH or a pharmaceuticallyacceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹,—CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CH(OR¹³O), —COR⁷, —CR⁷(OR¹²)₂,—CR⁷(OR¹³O), or —Si(C₁-C₆)₃, where R⁷ is an alkyl, cycloalkyl or alkenylgroup containing 1 to 5 carbons, R⁸ is an alkyl group of 1 to 10 carbonsor (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R⁸ is phenyl or loweralkyphenyl, R⁹ and R¹⁰ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl,hydroxyphenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or loweralkylphenyl, R¹² is lower alkyl, and R¹³ is divalent alkyl radical of 2to 5 carbons, and R¹⁴ is H, alkyl of 1 to 10 carbons, fluoro-substitutedalkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3double bonds.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XVIII:

wherein R¹ is independently H, lower alkyl of 1 to 6 carbons, or lowerfluoroalkyl of 1 to 6 carbons; R¹* is hydrogen or C₁₋₆-alkyl; R²* isindependently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of1 to 6 carbons; R³* is hydrogen, lower alkyl of 1 to 6 carbons, fluorosubstituted lower alkyl of 1 to 6 carbons or halogen; X¹* is an oxo (═O)or a thione (═S) group; A* is hydrogen, —COOH or a pharmaceuticallyacceptable salt thereof, —COOR^(B), —CONR⁹R¹⁰, where R⁸ is an alkylgroup of 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl grouphas 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R⁸ isphenyl or lower alkylphenyl, R⁹ and R¹⁰ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl, hydroxyphenyl or lower alkylphenyl, and the cyclopropyl groupis attached to the 6 or 7 position of the tetrahydroquinoline moiety,and R¹⁴* is alkyl of 1 to 10 carbons or fluoro-substituted alkyl of 1 to10 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formulae XIX, XX, or XXI:

where X is O, S, or (CR¹R¹)_(n) where n is 0, 1 or 2; Y is a bivalentradical having the structure of Formulae XXII or XXIII where o is aninteger between 1 through 4

or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1to 3 heteroatoms selected from N, S and O, the aryl or heteroaryl groupsbeing unsubstituted, or substituted with 1 to 3 C₁₋₆ alkyl or with 1 to3 C₁₋₆ fluoroalkyl groups with the proviso that when the compound is inaccordance with Formula II then Y is not a 5 or 6 membered ring; X¹ is Sor NH; R¹ is independently H, lower alkyl of 1 to 6 carbons, or lowerfluoroalkyl of 1 to 6 carbons; R² is independently H, lower alkyl of 1to 6 carbons, OR¹, adamantly, or lower fluoroalkyl of 1 to 6 carbons, orthe two R² groups jointly represent an oxo (═O) group with the provisothat when the compound is in accordance with Formula II then at leastone of the R² substituents is branched-chain alkyl or adamantly; R³ ishydrogen, lower alkyl of 1 to 6 carbons, OR¹, fluoro substituted loweralkyl of 1 to 6 carbons or halogen, NO₂, NH₂, —NHCO(C₁-C₆) alkyl, or—NHCO(C₁-C₆) alkenyl; A is —COOH or a pharmaceutically acceptable saltthereof, COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO,—CH(OR¹²)₂, —CH(OR¹³O), —COR⁷, —CR⁷(OR¹²)₂, —CR⁷(OR¹³O), or—Si(C₁₋₆alkyl)₃, where R⁷ is an alkyl, cycloalkyl or alkenyl groupcontaining 1 to 5 carbons, R⁸ is an alkyl group of 1 to 10 carbons or(trimethylsilyl) alkyl where the alkyl group has 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R⁸ is phenyl or loweralkylphenyl, R⁹ and R¹⁰ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl,hydroxyphenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ isdivalent alkyl radical of 2-5 carbons, and R¹⁴ is alkyl of 1 to 10carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbonsand 1 to 3 triple bonds, carbocyclic aryl selected from the groupconsisting of phenyl, C₁-C₁₀-alkylphenyl, naphthyl,C₁-C₁₀-alkylnaphthyl, phenyl-C₁-C₁₀-alkyl, naphthyl-C₁-C₁₀ alkyl,C₁-C₁₀-alkenylphenyl having 1 to 3 double bonds, C₁-C₁₀-alkynylphenylhaving 1 to 3 triple bonds, phenyl-C₁-C₁₀ alkenyl having 1 to 3 doublebonds, phenyl-C₁-C₁₀ alkenyl having 1 to 3 triple bonds, hydroxyl alkylof 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triplebonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2 to 10carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbonsand 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenylhaving 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2to 10 carbons and 1 to 3 triple bonds where the acyl group isrepresented by —COR⁸, or R¹⁴ is a 5 or 6 membered heteroaryl grouphaving 1 to 3 heteroatoms, the heteroatoms being selected from a groupconsisting of O, S, and N, the heteroaryl group being unsubstituted orsubstituted with a C₁-C₁₀ alkyl group, with a C₁-C₁₀ fluoroalkyl group,or with halogen, and the dashed line in Formula XXII represents a bondor absence of a bond.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XXIV:

wherein R is H, lower alkyl of 1 to 6 carbons, or a pharmaceuticallyacceptable salt of the compound.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XXV:

wherein R is H, lower alkyl of 1 to 6 carbons, and R¹ is iso-propyl ortertiary-butyl, or a pharmaceutically acceptable salt of the compound.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XXVI:

wherein R is H, lower alkyl of 1 to 6 carbons, and R¹ is iso-propyl,n-butyl or tertiary-butyl, or a pharmaceutically acceptable salt of thecompound.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XXVII:

where X is O or S; Y is a bivalent cycloalkyl or cycloalkenyl radicaloptionally substituted with one to four R⁴ groups, the cycloalkenylradical having 5 to 6 carbons and one double bond, or Y is a bivalentaryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatomsselected from N, S and O, the aryl or heteroaryl groups optionallysubstituted with 1 to 4 R⁴ groups with the proviso that the cycloalkylor the cycloalkenyl radical is not substituted on the same carbon withthe condensed cyclic moiety and with the diene containing moiety; R¹ isindependently H, alkyl of 1 to 6 carbons, or fluoroalkyl of 1 to 6carbons; R² is independently H, alkyl of 1 to 8 carbons, or fluoroalkylof 1 to 8 carbons; R¹² is independently H, alkyl of 1 to 8 carbons, orfluoroalkyl of 1 to 8 carbons; R³ is hydrogen, alkyl of 1 to 10 carbons,fluoro substituted alkyl of 1 to 10 carbons, halogen, alkoxy of 1 to 10carbons, or alkylthio of 1 to 10 carbons; NO₂, NH₂, —NHCO(C₁-C₆) alkyl,—NHCO(C₁-C₆) alkenyl, —NR¹H or N(R¹)₂, benzyloxy, C₁-C₆alkyl-substituted benzyloxy, or R³ is selected from the groups shownbelow:

R⁴ is H, halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10carbons; m is an integer having the values of 0 to 3; r is an integerhaving the values of 1 to 10; s is an integer having the values 1 to 4;t is an integer having the values 1 to 5;

represents a 5 or 6 membered heteroaryl ring having 1 to 3 heteroatomsselected from the group consisting of N, S and O; B is hydrogen, COOH ora pharmaceutically acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH,—CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂,—CR⁷OR¹³O, or trilower alkylsilyl, where R⁷ is an alkyl, cycloalkyl oralkenyl group containing 1 to 5 carbons, R⁸ is an alkyl group of 1 to 10carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkylwhere the alkyl group has 1 to 10 carbons, or R⁸ is phenyl or loweralkylphenyl, R⁹ and R¹⁰ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or loweralkylphenyl, R¹¹ is lower alkyl, phenyl or lower alkylphenyl, R¹² islower alkyl, and R¹³ is divalent alkyl radical of 2 to 5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XXVIII:

wherein R¹ is H or methyl; R⁸ is H, alkyl of 1 to 6 carbons, or apharmaceutically acceptable cation, and R³ is hydrogen, alkyl of 1 to 10carbons, halogen, alkoxy of 1 to 10 carbons, or R³ is selected from thegroups shown below:

where R⁴ is H, halogen, alkyl of 1 to 10 carbons, carbons, alkoxy of 1to 10; r is an integer having the values of 1 to 10; s is an integerhaving the values 1 to 4;

represents a 5 or 6 membered heteroaryl ring having 1 to 3 heteroatomsselected from the group consisting of N, S and O, and t is an integerhaving the values 1 to 5.

In an aspect of this embodiment, a RXR agonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid, and has the structure of formula XXIX:

Aspects of the present specification provide, in part, a RXR agonisthaving activity that promotes Treg cell differentiation. In aspects ofthis embodiment, a RXR agonist promotes Treg cell differentiation by atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 100%, atleast 200%, at least 300%, at least 400%, or at least 500%. In otheraspects of this embodiment, a RXR agonist promotes Treg celldifferentiation by about 10% to about 25%, about 10% to about 50%, about10% to about 75%, about 10% to about 100%, about 10% to about 200%,about 10% to about 300%, about 10% to about 400%, about 10% to about500%, about 25% to about 50%, about 25% to about 75%, about 25% to about100%, about 25% to about 200%, about 25% to about 300%, about 25% toabout 400%, about 25% to about 500%, about 50% to about 100%, about 50%to about 200%, about 50% to about 300%, about 50% to about 400%, orabout 50% to about 500%.

In an embodiment, a RXR agonist has activity that results in increasedFoxp3 expression in cells exposed to the RXR agonist. In aspects of thisembodiment, a RXR agonist increases Foxp3 expression in cells by atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 100%, atleast 200%, at least 300%, at least 400%, or at least 500%, relative tocells not exposed to the same RXR agonist. In other aspects of thisembodiment, a RXR agonist increases Foxp3 expression in cells by about10% to about 25%, about 10% to about 50%, about 10% to about 75%, about10% to about 100%, about 10% to about 200%, about 10% to about 300%,about 10% to about 400%, about 10% to about 500%, about 25% to about50%, about 25% to about 75%, about 25% to about 100%, about 25% to about200%, about 25% to about 300%, about 25% to about 400%, about 25% toabout 500%, about 50% to about 100%, about 50% to about 200%, about 50%to about 300%, about 50% to about 400%, or about 50% to about 500%,relative to cells not exposed to the same RXR agonist.

In another aspect of this embodiment, a RXR agonist has activity thatresults in increased Foxp3 expression in naive CD4⁺ CD25⁻ FoxP3⁻ cellscultured under Treg cell differentiation conditions. In other aspects ofthis embodiment, a RXR agonist increases Foxp3 expression in naive CD4⁺CD25⁻ FoxP3⁻ cells cultured under Treg cell differentiation by at least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least60%, at least 70%, at least 80%, at least 90%, at least 100%, at least200%, at least 300%, at least 400%, or at least 500%, relative to naiveCD4⁺ CD25⁻ FoxP3⁻ cells cultured under Treg cell differentiation notexposed to the same RXR agonist. In yet other aspects of thisembodiment, a RXR agonist increases Foxp3 expression in naive CD4⁺ CD25⁻FoxP3⁻ cells cultured under Treg cell differentiation by about 10% toabout 25%, about 10% to about 50%, about 10% to about 75%, about 10% toabout 100%, about 10% to about 200%, about 10% to about 300%, about 10%to about 400%, about 10% to about 500%, about 25% to about 50%, about25% to about 75%, about 25% to about 100%, about 25% to about 200%,about 25% to about 300%, about 25% to about 400%, about 25% to about500%, about 50% to about 100%, about 50% to about 200%, about 50% toabout 300%, about 50% to about 400%, or about 50% to about 500%,relative to naive CD4⁺ CD25⁻ FoxP3⁻ cells cultured under Treg celldifferentiation not exposed to the same RXR agonist.

In an embodiment, a RXR agonist has activity that results in increasedα4β7 expression in cells exposed to the RXR agonist. In aspects of thisembodiment, a RXR agonist increases α4β7 expression in cells by at least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least60%, at least 70%, at least 80%, at least 90%, at least 100%, at least200%, at least 300%, at least 400%, or at least 500%, relative to cellsnot exposed to the same RXR agonist. In other aspects of thisembodiment, a RXR agonist increases α4β7 expression in cells by about10% to about 25%, about 10% to about 50%, about 10% to about 75%, about10% to about 100%, about 10% to about 200%, about 10% to about 300%,about 10% to about 400%, about 10% to about 500%, about 25% to about50%, about 25% to about 75%, about 25% to about 100%, about 25% to about200%, about 25% to about 300%, about 25% to about 400%, about 25% toabout 500%, about 50% to about 100%, about 50% to about 200%, about 50%to about 300%, about 50% to about 400%, or about 50% to about 500%,relative to cells not exposed to the same RXR agonist.

In another aspect of this embodiment, a RXR agonist has activity thatresults in increased α4β7 expression in naive CD4⁺ CD25⁻ FoxP3⁻ cellscultured under Treg cell differentiation conditions. In other aspects ofthis embodiment, a RXR agonist increases α4β7 expression in naive CD4⁺CD25⁻ FoxP3⁻ cells cultured under Treg cell differentiation by at least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least60%, at least 70%, at least 80%, at least 90%, at least 100%, at least200%, at least 300%, at least 400%, or at least 500%, relative to naiveCD4⁺ CD25⁻ FoxP3⁻ cells cultured under Treg cell differentiation notexposed to the same RXR agonist. In yet other aspects of thisembodiment, a RXR agonist increases α4β7 expression in naive CD4⁺ CD25⁻FoxP3⁻ cells cultured under Treg cell differentiation by about 10% toabout 25%, about 10% to about 50%, about 10% to about 75%, about 10% toabout 100%, about 10% to about 200%, about 10% to about 300%, about 10%to about 400%, about 10% to about 500%, about 25% to about 50%, about25% to about 75%, about 25% to about 100%, about 25% to about 200%,about 25% to about 300%, about 25% to about 400%, about 25% to about500%, about 50% to about 100%, about 50% to about 200%, about 50% toabout 300%, about 50% to about 400%, or about 50% to about 500%,relative to naive CD4⁺ CD25⁻ FoxP3⁻ cells cultured under Treg celldifferentiation not exposed to the same RXR agonist.

Aspects of the present specification provide, in part, a RXR agonisthaving activity that inhibits Th17 cell differentiation. In aspects ofthis embodiment, a RXR agonist inhibits Th17 cell differentiation by atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 100%, atleast 200%, at least 300%, at least 400%, or at least 500%. In otheraspects of this embodiment, a RXR agonist inhibits Th17 celldifferentiation by about 10% to about 25%, about 10% to about 50%, about10% to about 75%, about 10% to about 100%, about 10% to about 200%,about 10% to about 300%, about 10% to about 400%, about 10% to about500%, about 25% to about 50%, about 25% to about 75%, about 25% to about100%, about 25% to about 200%, about 25% to about 300%, about 25% toabout 400%, about 25% to about 500%, about 50% to about 100%, about 50%to about 200%, about 50% to about 300%, about 50% to about 400%, orabout 50% to about 500%.

In an embodiment, a RXR agonist has activity that results in decreasedIL-17A expression in cells exposed to the RXR agonist. In aspects ofthis embodiment, a RXR agonist decreases IL-17A expression in cells byat least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 100%, atleast 200%, at least 300%, at least 400%, or at least 500%, relative tocells not exposed to the same RXR agonist. In other aspects of thisembodiment, a RXR agonist decreases IL-17A expression in cells by about10% to about 25%, about 10% to about 50%, about 10% to about 75%, about10% to about 100%, about 10% to about 200%, about 10% to about 300%,about 10% to about 400%, about 10% to about 500%, about 25% to about50%, about 25% to about 75%, about 25% to about 100%, about 25% to about200%, about 25% to about 300%, about 25% to about 400%, about 25% toabout 500%, about 50% to about 100%, about 50% to about 200%, about 50%to about 300%, about 50% to about 400%, or about 50% to about 500%,relative to cells not exposed to the same RXR agonist.

In another aspect of this embodiment, a RXR agonist has activity thatresults in decreased IL-17A expression in naive CD4⁺ CD25⁻ FoxP3⁻ cellscultured under Th17 cell differentiation conditions. In other aspects ofthis embodiment, a RXR agonist decreases IL-17A expression in naive CD4⁺CD25⁻ FoxP3⁻ cells cultured under Th17 cell differentiation by at least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least60%, at least 70%, at least 80%, at least 90%, at least 100%, at least200%, at least 300%, at least 400%, or at least 500%, relative to naiveCD4⁺ CD25⁻ FoxP3⁻ cells cultured under Th17 cell differentiation notexposed to the same RXR agonist. In yet other aspects of thisembodiment, a RXR agonist decreases IL-17A expression in naive CD4⁺CD25⁻ FoxP3⁻ cells cultured under Th17 cell differentiation by about 10%to about 25%, about 10% to about 50%, about 10% to about 75%, about 10%to about 100%, about 10% to about 200%, about 10% to about 300%, about10% to about 400%, about 10% to about 500%, about 25% to about 50%,about 25% to about 75%, about 25% to about 100%, about 25% to about200%, about 25% to about 300%, about 25% to about 400%, about 25% toabout 500%, about 50% to about 100%, about 50% to about 200%, about 50%to about 300%, about 50% to about 400%, or about 50% to about 500%,relative to naive CD4⁺ CD25⁻ FoxP3⁻ cells cultured under Th17 celldifferentiation not exposed to the same RXR agonist.

Aspects of the present specification provide, in part, a RXR agonisthaving activity that both promotes Treg cell differentiation andinhibits Th17 cell differentiation. In aspects of this embodiment, a RXRagonist promotes Treg cell differentiation by at least 10%, at least20%, at least 30%, at least 40%, at least 50%, at least 60%, at least70%, at least 80%, at least 90%, at least 100%, at least 200%, at least300%, at least 400%, or at least 500% as well as inhibits Th17 celldifferentiation by at least 10%, at least 20%, at least 30%, at least40%, at least 50%, at least 60%, at least 70%, at least 80%, at least90%, at least 100%, at least 200%, at least 300%, at least 400%, or atleast 500%. In other aspects of this embodiment, a RXR agonist promotesTreg cell differentiation by about 10% to about 25%, about 10% to about50%, about 10% to about 75%, about 10% to about 100%, about 10% to about200%, about 10% to about 300%, about 10% to about 400%, about 10% toabout 500%, about 25% to about 50%, about 25% to about 75%, about 25% toabout 100%, about 25% to about 200%, about 25% to about 300%, about 25%to about 400%, about 25% to about 500%, about 50% to about 100%, about50% to about 200%, about 50% to about 300%, about 50% to about 400%, orabout 50% to about 500%, as well as inhibits Th17 cell differentiationby about 10% to about 25%, about 10% to about 50%, about 10% to about75%, about 10% to about 100%, about 10% to about 200%, about 10% toabout 300%, about 10% to about 400%, about 10% to about 500%, about 25%to about 50%, about 25% to about 75%, about 25% to about 100%, about 25%to about 200%, about 25% to about 300%, about 25% to about 400%, about25% to about 500%, about 50% to about 100%, about 50% to about 200%,about 50% to about 300%, about 50% to about 400%, or about 50% to about500%.

In an embodiment, a RXR agonist has activity that results in increasedFoxP3 and/or α4β7 expression as well as decreases IL-17A expression incells exposed to the RXR agonist. In aspects of this embodiment, a RXRagonist increases FoxP3 and/or α4β7 expression in cells by at least 10%,at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%, at least 80%, at least 90%, at least 100%, at least 200%, atleast 300%, at least 400%, or at least 500%, as well as decreases IL-17Aexpression in cells by at least 10%, at least 20%, at least 30%, atleast 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, at least 100%, at least 200%, at least 300%, at least 400%,or at least 500%, relative to cells not exposed to the same RXR agonist.In other aspects of this embodiment, a RXR agonist increases FoxP3and/or α4β7 expression in cells by about 10% to about 25%, about 10% toabout 50%, about 10% to about 75%, about 10% to about 100%, about 10% toabout 200%, about 10% to about 300%, about 10% to about 400%, about 10%to about 500%, about 25% to about 50%, about 25% to about 75%, about 25%to about 100%, about 25% to about 200%, about 25% to about 300%, about25% to about 400%, about 25% to about 500%, about 50% to about 100%,about 50% to about 200%, about 50% to about 300%, about 50% to about400%, or about 50% to about 500%, as well as decreases IL-17A expressionin cells by about 10% to about 25%, about 10% to about 50%, about 10% toabout 75%, about 10% to about 100%, about 10% to about 200%, about 10%to about 300%, about 10% to about 400%, about 10% to about 500%, about25% to about 50%, about 25% to about 75%, about 25% to about 100%, about25% to about 200%, about 25% to about 300%, about 25% to about 400%,about 25% to about 500%, about 50% to about 100%, about 50% to about200%, about 50% to about 300%, about 50% to about 400%, or about 50% toabout 500%, relative to cells not exposed to the same RXR agonist.

In another aspect of this embodiment, a RXR agonist has activity thatresults in increased FoxP3 and/or α4β7 expression in naive CD4⁺ CD25⁻FoxP3⁻ cells cultured under Treg cell differentiation conditions as wellas decreases IL-17A expression in naive CD4⁺ CD25⁻ FoxP3⁻ cells culturedunder Th17 cell differentiation conditions. In other aspects of thisembodiment, a RXR agonist increases FoxP3 and/or α4β7 expression innaive CD4⁺ CD25⁻ FoxP3 cells cultured under Treg cell differentiation byat least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 100%, atleast 200%, at least 300%, at least 400%, or at least 500%, relative tonaive CD4⁺ CD25⁻ FoxP3⁻ cells cultured under Treg cell differentiationnot exposed to the same RXR agonist as well as decreases IL-17Aexpression in naive CD4⁺ CD25⁻ FoxP3⁻ cells cultured under Th17 celldifferentiation by at least 10%, at least 20%, at least 30%, at least40%, at least 50%, at least 60%, at least 70%, at least 80%, at least90%, at least 100%, at least 200%, at least 300%, at least 400%, or atleast 500%, relative to naive CD4⁺ CD25⁻ FoxP3⁻ cells cultured underTh17 cell differentiation not exposed to the same RXR agonist.

In yet other aspects of this embodiment, a RXR agonist increases FoxP3and/or α4β7 expression in naive CD4⁺ CD25⁻ FoxP3⁻ cells cultured underTreg cell differentiation by about 10% to about 25%, about 10% to about50%, about 10% to about 75%, about 10% to about 100%, about 10% to about200%, about 10% to about 300%, about 10% to about 400%, about 10% toabout 500%, about 25% to about 50%, about 25% to about 75%, about 25% toabout 100%, about 25% to about 200%, about 25% to about 300%, about 25%to about 400%, about 25% to about 500%, about 50% to about 100%, about50% to about 200%, about 50% to about 300%, about 50% to about 400%, orabout 50% to about 500%, relative to naive CD4⁺ CD25⁻ FoxP3⁻ cellscultured under Treg cell differentiation not exposed to the same RXRagonist as well as decreases IL-17A expression in naive CD4⁺ CD25⁻FoxP3⁻ cells cultured under Th17 cell differentiation by about 10% toabout 25%, about 10% to about 50%, about 10% to about 75%, about 10% toabout 100%, about 10% to about 200%, about 10% to about 300%, about 10%to about 400%, about 10% to about 500%, about 25% to about 50%, about25% to about 75%, about 25% to about 100%, about 25% to about 200%,about 25% to about 300%, about 25% to about 400%, about 25% to about500%, about 50% to about 100%, about 50% to about 200%, about 50% toabout 300%, about 50% to about 400%, or about 50% to about 500%,relative to naive CD4⁺ CD25⁻ FoxP3⁻ cells cultured under Th17 celldifferentiation not exposed to the same RXR agonist.

Aspects of the present specification provide, in part, a compositioncomprising a RXR agonist. A RXR agonist includes the compounds disclosedherein. The compositions disclosed herein may, or may not, comprise anynumber and combination of compounds disclosed herein. For instance, acomposition can comprise, e.g., two or more compounds disclosed herein,three or more compounds disclosed herein, four or more compoundsdisclosed herein, or five or more compounds disclosed herein.

A compound disclosed herein, or a composition comprising such acompound, is generally administered to an individual as a pharmaceuticalcomposition. Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound as disclosedherein, or a pharmaceutically acceptable acid addition salt thereof, asan active ingredient, with conventional acceptable pharmaceuticalexcipients, and by preparation of unit dosage forms suitable fortherapeutic use. As used herein, the term “pharmaceutical composition”and refers to a therapeutically effective concentration of an activecompound, such as, e.g., any of the compounds disclosed herein.Preferably, the pharmaceutical composition does not produce an adverse,allergic, or other untoward or unwanted reaction when administered to anindividual. A pharmaceutical composition disclosed herein is useful formedical and veterinary applications. A pharmaceutical composition may beadministered to an individual alone, or in combination with othersupplementary active compounds, agents, drugs or hormones. Thepharmaceutical compositions may be manufactured using any of a varietyof processes, including, without limitation, conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, and lyophilizing. The pharmaceuticalcomposition can take any of a variety of forms including, withoutlimitation, a sterile solution, suspension, emulsion, lyophilizate,tablet, pill, pellet, capsule, powder, syrup, elixir, or any otherdosage form suitable for administration.

A pharmaceutical composition produced using the methods disclosed hereinmay be a liquid formulation, semi-solid formulation, or a solidformulation. A formulation disclosed herein can be produced in a mannerto form one phase, such as, e.g., an oil or a solid. Alternatively, aformulation disclosed herein can be produced in a manner to form twophase, such as, e.g., an emulsion. A pharmaceutical compositiondisclosed herein intended for such administration may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions.

Liquid formulations suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethyleneglycol (PEG), glycerol, and the like), suitable mixturesthereof, vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate. Proper fluidity can be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersions and by the use ofsurfactants.

Semi-solid formulations suitable for topical administration include,without limitation, ointments, creams, salves, and gels. In such solidformulations, the active compound may be admixed with at least one inertcustomary excipient (or carrier) such as, a lipid and/or polyethyleneglycol.

Solid formulations suitable for oral administration include capsules,tablets, pills, powders and granules. In such solid formulations, theactive compound may be admixed with at least one inert customaryexcipient (or carrier) such as sodium citrate or dicalcium phosphate or(a) fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol and silicic acid, (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose and acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates andsodium carbonate, (e) solution retarders, as for example, paraffin, (f)absorption accelerators, as for example, quaternary ammonium compounds,(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate, (h) adsorbents, as for example, kaolin and bentonite, and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate or mixturesthereof. In the case of capsules, tablets and pills, the dosage formsmay also comprise buffering agents.

In liquid and semi-solid formulations, a concentration of a therapeuticcompound disclosed herein typically may be between about 50 mg/mL toabout 1,000 mg/mL. In aspects of this embodiment, a therapeuticallyeffective amount of a therapeutic compound disclosed herein may be from,e.g., about 50 mg/mL to about 100 mg/mL, about 50 mg/mL to about 200mg/mL, about 50 mg/mL to about 300 mg/mL, about 50 mg/mL to about 400mg/mL, about 50 mg/mL to about 500 mg/mL, about 50 mg/mL to about 600mg/mL, about 50 mg/mL to about 700 mg/mL, about 50 mg/mL to about 800mg/mL, about 50 mg/mL to about 900 mg/mL, about 50 mg/mL to about 1,000mg/mL, about 100 mg/mL to about 200 mg/mL, about 100 mg/mL to about 300mg/mL, about 100 mg/mL to about 400 mg/mL, about 100 mg/mL to about 500mg/mL, about 100 mg/mL to about 600 mg/mL, about 100 mg/mL to about 700mg/mL, about 100 mg/mL to about 800 mg/mL, about 100 mg/mL to about 900mg/mL, about 100 mg/mL to about 1,000 mg/mL, about 200 mg/mL to about300 mg/mL, about 200 mg/mL to about 400 mg/mL, about 200 mg/mL to about500 mg/mL, about 200 mg/mL to about 600 mg/mL, about 200 mg/mL to about700 mg/mL, about 200 mg/mL to about 800 mg/mL, about 200 mg/mL to about900 mg/mL, about 200 mg/mL to about 1,000 mg/mL, about 300 mg/mL toabout 400 mg/mL, about 300 mg/mL to about 500 mg/mL, about 300 mg/mL toabout 600 mg/mL, about 300 mg/mL to about 700 mg/mL, about 300 mg/mL toabout 800 mg/mL, about 300 mg/mL to about 900 mg/mL, about 300 mg/mL toabout 1,000 mg/mL, about 400 mg/mL to about 500 mg/mL, about 400 mg/mLto about 600 mg/mL, about 400 mg/mL to about 700 mg/mL, about 400 mg/mLto about 800 mg/mL, about 400 mg/mL to about 900 mg/mL, about 400 mg/mLto about 1,000 mg/mL, about 500 mg/mL to about 600 mg/mL, about 500mg/mL to about 700 mg/mL, about 500 mg/mL to about 800 mg/mL, about 500mg/mL to about 900 mg/mL, about 500 mg/mL to about 1,000 mg/mL, about600 mg/mL to about 700 mg/mL, about 600 mg/mL to about 800 mg/mL, about600 mg/mL to about 900 mg/mL, or about 600 mg/mL to about 1,000 mg/mL.

In semi-solid and solid formulations, an amount of a therapeuticcompound disclosed herein typically may be between about 0.01% to about45% by weight. In aspects of this embodiment, an amount of a therapeuticcompound disclosed herein may be from, e.g., about 0.1% to about 45% byweight, about 0.1% to about 40% by weight, about 0.1% to about 35% byweight, about 0.1% to about 30% by weight, about 0.1% to about 25% byweight, about 0.1% to about 20% by weight, about 0.1% to about 15% byweight, about 0.1% to about 10% by weight, about 0.1% to about 5% byweight, about 1% to about 45% by weight, about 1% to about 40% byweight, about 1% to about 35% by weight, about 1% to about 30% byweight, about 1% to about 25% by weight, about 1% to about 20% byweight, about 1% to about 15% by weight, about 1% to about 10% byweight, about 1% to about 5% by weight, about 5% to about 45% by weight,about 5% to about 40% by weight, about 5% to about 35% by weight, about5% to about 30% by weight, about 5% to about 25% by weight, about 5% toabout 20% by weight, about 5% to about 15% by weight, about 5% to about10% by weight, about 10% to about 45% by weight, about 10% to about 40%by weight, about 10% to about 35% by weight, about 10% to about 30% byweight, about 10% to about 25% by weight, about 10% to about 20% byweight, about 10% to about 15% by weight, about 15% to about 45% byweight, about 15% to about 40% by weight, about 15% to about 35% byweight, about 15% to about 30% by weight, about 15% to about 25% byweight, about 15% to about 20% by weight, about 20% to about 45% byweight, about 20% to about 40% by weight, about 20% to about 35% byweight, about 20% to about 30% by weight, about 20% to about 25% byweight, about 25% to about 45% by weight, about 25% to about 40% byweight, about 25% to about 35% by weight, or about 25% to about 30% byweight.

A pharmaceutical composition disclosed herein can optionally include apharmaceutically acceptable carrier that facilitates processing of anactive compound into pharmaceutically acceptable compositions. As usedherein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio. As used herein, theterm “pharmacologically acceptable carrier” is synonymous with“pharmacological carrier” and refers to any carrier that hassubstantially no long term or permanent detrimental effect whenadministered and encompasses terms such as “pharmacologically acceptablevehicle, stabilizer, diluent, additive, auxiliary, or excipient.” Such acarrier generally is mixed with an active compound or permitted todilute or enclose the active compound and can be a solid, semi-solid, orliquid agent. It is understood that the active compounds can be solubleor can be delivered as a suspension in the desired carrier or diluent.Any of a variety of pharmaceutically acceptable carriers can be usedincluding, without limitation, aqueous media such as, e.g., water,saline, glycine, hyaluronic acid and the like; solid carriers such as,e.g., starch, magnesium stearate, mannitol, sodium saccharin, talcum,cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate,and the like; solvents; dispersion media; coatings; antibacterial andantifungal agents; isotonic and absorption delaying agents; or any otherinactive ingredient. Selection of a pharmacologically acceptable carriercan depend on the mode of administration. Except insofar as anypharmacologically acceptable carrier is incompatible with the activecompound, its use in pharmaceutically acceptable compositions iscontemplated. Non-limiting examples of specific uses of suchpharmaceutical carriers can be found in Pharmaceutical Dosage Forms andDrug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams& Wilkins Publishers, 7^(th) ed. 1999); Remington: The Science andPractice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams &Wilkins, 20^(th) ed. 2000); Goodman & Gilman's The Pharmacological Basisof Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional,10^(th) ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C.Rowe et al., APhA Publications, 4^(th) edition 2003). These protocolsare routine and any modifications are well within the scope of oneskilled in the art and from the teaching herein.

A pharmaceutical composition disclosed herein can optionally include,without limitation, other pharmaceutically acceptable components (orpharmaceutical components), including, without limitation, buffers,preservatives, tonicity adjusters, salts, antioxidants, osmolalityadjusting agents, physiological substances, pharmacological substances,bulking agents, emulsifying agents, wetting agents, sweetening orflavoring agents, and the like. Various buffers and means for adjustingpH can be used to prepare a pharmaceutical composition disclosed herein,provided that the resulting preparation is pharmaceutically acceptable.Such buffers include, without limitation, acetate buffers, boratebuffers, citrate buffers, phosphate buffers, neutral buffered saline,and phosphate buffered saline. It is understood that acids or bases canbe used to adjust the pH of a composition as needed. Pharmaceuticallyacceptable antioxidants include, without limitation, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole, and butylated hydroxytoluene. Useful preservativesinclude, without limitation, benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilizedoxy chloro composition, such as, e.g., sodium chlorite and chelants,such as, e.g., DTPA or DTPA-bisamide, calcium DTPA, andCaNaDTPA-bisamide. Tonicity adjustors useful in a pharmaceuticalcomposition include, without limitation, salts such as, e.g., sodiumchloride, potassium chloride, mannitol or glycerin and otherpharmaceutically acceptable tonicity adjustor. The pharmaceuticalcomposition may be provided as a salt and can be formed with many acids,including but not limited to, hydrochloric, sulfuric, acetic, lactic,tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueousor other protonic solvents than are the corresponding free base forms.It is understood that these and other substances known in the art ofpharmacology can be included in a pharmaceutical composition useful inthe invention.

A compound disclosed herein, or a composition comprising such acompound, may also be incorporated into a drug delivery platform inorder to achieve a controlled compound release profile over time. Such adrug delivery platform comprises a compound disclosed herein dispersedwithin a polymer matrix, typically a biodegradable, bioerodible, and/orbioresorbable polymer matrix. As used herein, the term “polymer” refersto synthetic homo- or copolymers, naturally occurring homo- orcopolymers, as well as synthetic modifications or derivatives thereofhaving a linear, branched or star structure. Copolymers can be arrangedin any form, such as, e.g., random, block, segmented, tapered blocks,graft, or triblock. Polymers are generally condensation polymers.Polymers can be further modified to enhance their mechanical ordegradation properties by introducing cross-linking agents or changingthe hydrophobicity of the side residues. If crosslinked, polymers areusually less than 5% crosslinked, usually less than 1% crosslinked.

Suitable polymers include, without limitation, alginates, aliphaticpolyesters, polyalkylene oxalates, polyamides, polyamidoesters,polyanhydrides, polycarbonates, polyesters, polyethylene glycol,polyhydroxyaliphatic carboxylic acids, polyorthoesters, polyoxaesters,polypeptides, polyphosphazenes, polysaccharides, and polyurethanes. Thepolymer usually comprises at least about 10% (w/w), at least about 20%(w/w), at least about 30% (w/w), at least about 40% (w/w), at leastabout 50% (w/w), at least about 60% (w/w), at least about 70% (w/w), atleast about 80% (w/w), or at least about 90% (w/w) of the drug deliveryplatform. Examples of biodegradable, bioerodible, and/or bioresorbablepolymers and methods useful to make a drug delivery platform aredescribed in, e.g., Drost, et. al., Controlled Release Formulation, U.S.Pat. No. 4,756,911; Smith, et. al., Sustained Release Drug DeliveryDevices, U.S. Pat. No. 5,378,475; Wong and Kochinke, Formulation forControlled Release of Drugs by Combining Hyrophilic and HydrophobicAgents, U.S. Pat. No. 7,048,946; Hughes, et. al., Compositions andMethods for Localized Therapy of the Eye, U.S. Patent Publication2005/0181017; Hughes, Hypotensive Lipid-Containing BiodegradableIntraocular Implants and Related Methods, U.S. Patent Publication2005/0244464; Altman, et al., Silk Fibroin Hydrogels and Uses Thereof,U.S. Patent Publication 2011/0008437; each of which is incorporated byreference in its entirety.

In aspects of this embodiment, a polymer composing the matrix is apolypeptide such as, e.g., silk fibroin, keratin, or collagen. In otheraspects of this embodiment, a polymer composing the matrix is apolysaccharide such as, e.g., cellulose, agarose, elastin, chitosan,chitin, or a glycosaminoglycan like chondroitin sulfate, dermatansulfate, keratan sulfate, or hyaluronic acid. In yet other aspects ofthis embodiment, a polymer composing the matrix is a polyester such as,e.g., D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid,caprolactone, and combinations thereof.

One of ordinary skill in the art appreciates that the selection of asuitable polymer for forming a suitable disclosed drug delivery platformdepends on several factors. The more relevant factors in the selectionof the appropriate polymer(s), include, without limitation,compatibility of polymer with drug, desired release kinetics of drug,desired biodegradation kinetics of platform at implantation site,desired bioerodible kinetics of platform at implantation site, desiredbioresorbable kinetics of platform at implantation site, in vivomechanical performance of platform, processing temperatures,biocompatibility of platform, and patient tolerance. Other relevantfactors that, to some extent, dictate the in vitro and in vivo behaviorof the polymer include the chemical composition, spatial distribution ofthe constituents, the molecular weight of the polymer and the degree ofcrystallinity.

A drug delivery platform includes both a sustained release drug deliveryplatform and an extended release drug delivery platform. As used herein,the term “sustained release” refers to the release of a compounddisclosed herein over a period of about seven days or more. As usedherein, the term “extended release” refers to the release of a compounddisclosed herein over a period of time of less than about seven days.

In aspects of this embodiment, a sustained release drug deliveryplatform releases a compound disclosed herein with substantially firstorder release kinetics over a period of, e.g., about 7 days afteradministration, about 15 days after administration, about 30 days afteradministration, about 45 days after administration, about 60 days afteradministration, about 75 days after administration, or about 90 daysafter administration. In other aspects of this embodiment, a sustainedrelease drug delivery platform releases a compound disclosed herein withsubstantially first order release kinetics over a period of, e.g., atleast 7 days after administration, at least 15 days afteradministration, at least 30 days after administration, at least 45 daysafter administration, at least 60 days after administration, at least 75days after administration, or at least 90 days after administration.

In aspects of this embodiment, a drug delivery platform releases acompound disclosed herein with substantially first order releasekinetics over a period of, e.g., about 1 day after administration, about2 days after administration, about 3 days after administration, about 4days after administration, about 5 days after administration, or about 6days after administration. In other aspects of this embodiment, a drugdelivery platform releases a compound disclosed herein withsubstantially first order release kinetics over a period of, e.g., atmost 1 day after administration, at most 2 days after administration, atmost 3 days after administration, at most 4 days after administration,at most 5 days after administration, or at most 6 days afteradministration.

Aspects of the present invention provide, in part, an autoimmunedisorder. An autoimmune disorder arises from an overactive immuneresponse of the body against substances and tissues normally present inthe body resulting in a break in tolerance toward self-antigens. Inother words, the body actually attacks its own cells because the immunesystem mistakes some part of the body as a pathogen and attacks it.Characterized by the development of pathogenic T cell populationsinfiltrating the target organ or tissue, autoimmune disorders may berestricted to certain organs or involve a particular tissue in differentplaces.

Autoimmune diseases can be broadly divided into systemic andorgan-specific autoimmune disorders, depending on the principalclinico-pathologic features of each disease. Systemic autoimmunediseases include, without limitation, systemic lupus erythematosus(SLE), Sjögren's syndrome, Scleroderma, rheumatoid arthritis andpolymyositis. Local autoimmune diseases may be endocrinologic (DiabetesMellitus Type 1, Hashimoto's thyroiditis, Addison's disease etc.),dermatologic (pemphigus vulgaris), hematologic (autoimmune haemolyticanemia), neural (multiple sclerosis) or can involve virtually anycircumscribed mass of body tissue. Non-limiting examples of anautoimmune disorder that can be treated using a compound or acomposition disclosed herein include an acute disseminatedencephalomyelitis (ADEM), an Addison's disease, an allergy, allergicrhinitis, an Alzheimer's disease, an anti-phospholipid antibody syndrome(APS), an arthritis such as, e.g., a monoarthritis, an oligoarthritis,or a polyarthritis like an osteoarthritis, a rheumatoid arthritis, ajuvenile idiopathic arthritis, a septic arthritis, aspondyloarthropathy, a gout, a pseudogout, or Still's disease, anasthma, an autoimmune deficiency syndrome (AIDS), an autoimmunehemolytic anemia, an autoimmune hepatitis, an autoimmune inner eardisease, a bullous pemphigoid, a celiac disease, a Chagas disease, achronic obstructive pulmonary disease (COPD), a diabetes mellitus type 1(IDDM), an endometriosis, a gastrointestinal disorder such as, e.g., anirritable bowel disease or an inflammatory bowel disease like Crohn'sdisease or an ulcerative colitis, a Goodpasture's syndrome, a Graves'disease, a Guillain-Barré syndrome (GBS), a Hashimoto's thyroiditis, ahidradenitis suppurativa, an idiopathic thrombocytopenic purpura, aninterstitial cystitis, a lupus, such as, e.g., a discoid lupuserythematosus, a drug-induced lupus erythematosus. a lupus nephritis, aneonatal lupus, a subacute cutaneous lupus erythematosus, or a systemiclupus erythematosus, a morphea, a multiple sclerosis (MS), a myastheniagravis, a myopathy such as, e.g., a dermatomyositis, an inclusion bodymyositis, or a polymyositis, a myositis, a narcolepsy, a neuromyotonia,a Parkinson's disease, a pemphigus vulgaris, a pernicious anaemia, aprimary biliary cirrhosis, a psoriasis, a recurrent disseminatedencephalomyelitis, a rheumatic fever, a schizophrenia, a scleroderma, aSjögren's syndrome, a skin disorder such as, e.g., dermatitis, aneczema, a statis dermatitis, a hidradenitis suppurativa, a psoriasis, arosacea or a scleroderma, a tenosynovitis, a uveitis, vasculitis suchas, e.g., a Buerger's disease, a cerebral vasculitis, a Churg-Straussarteritis, a cryoglobulinemia, an essential cryoglobulinemic vasculitis,a giant cell arteritis, a Golfer's vasculitis, a Henoch-Schonleinpurpura, a hypersensitivity vasculitis, a Kawasaki disease, amicroscopic polyarteritis/polyangiitis, a polyarteritis nodosa, apolymyalgia rheumatica (PMR), a rheumatoid vasculitis, a Takayasuarteritis, or a Wegener's granulomatosis, or a vitiligo. See Pamela D.Van Schaack & Kenneth L. Tong, Treatment of Autoimmune Disorder with aNeurotoxin, U.S. Patent Publication 2006/138059, which is herebyincorporated by reference in its entirety.

One type of autoimmune disorder is an arthritis. Arthritis includes agroup of conditions involving damage to the joints of the body due tothe inflammation of the synovium including, without limitationosteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis,spondyloarthropathies like ankylosing spondylitis, reactive arthritis(Reiter's syndrome), psoriatic arthritis, enteropathic arthritisassociated with inflammatory bowel disease, Whipple's disease andBehcet's disease, septic arthritis, gout (also known as gouty arthritis,crystal synovitis, metabolic arthritis), pseudogout (calciumpyrophosphate deposition disease), and Still's disease. Arthritis canaffect a single joint (monoarthritis), two to four joints(oligoarthritis) or five or more joints (polyarthritis) and can beeither an auto-immune disease or a non-autoimmune disease.

Another type of autoimmune disorder is a myopathy. Myopathies are causedby problems with the immune system attacking components of the muscle,leading to signs of inflammation in the muscle Inflammatory myopathiesinclude, without limitation, dermatomyositis, inclusion body myositis,and polymyositis.

Another type of autoimmune disorder is a vasculitis. Vasculitis is avaried group of disorders featuring inflammation of a vessel wallincluding lymphatic vessels and blood vessels like veins (phlebitis),arteries (arteritis) and capillaries due to leukocyte migration andresultant damage. The inflammation may affect any size blood vessel,anywhere in the body. It may affect either arteries and/or veins. Theinflammation may be focal, meaning that it affects a single locationwithin a vessel; or it may be widespread, with areas of inflammationscattered throughout a particular organ or tissue, or even affectingmore than one organ system in the body. Vasculitis include, withoutlimitation, Buerger's disease (thromboangiitis obliterans), cerebralvasculitis (central nervous system vasculitis), Churg-Strauss arteritis,cryoglobulinemia, essential cryoglobulinemic vasculitis, giant cell(temporal) arteritis, Golfer's vasculitis, Henoch-Schonlein purpura,hypersensitivity vasculitis (allergic vasculitis), Kawasaki disease,microscopic polyarteritis/polyangiitis, polyarteritis nodosa,polymyalgia rheumatica (PMR), rheumatoid vasculitis, Takayasu arteritis,Wegener's granulomatosis, and vasculitis secondary to connective tissuedisorders like systemic lupus erythematosus (SLE), rheumatoid arthritis(RA), relapsing polychondritis, Behşet's disease, or other connectivetissue disorders, vasculitis secondary to viral infection.

Another type of autoimmune disorder is a skin disorder. Skin disordersinclude, without limitation, a dermatitis, including chronic actinicdermatitis, an eczema like atopic eczema, contact eczema, xeroticeczema, seborrhoeic dermatitis, dyshidrosis, discoid eczema, venouseczema, dermatitis herpetiformis, neurodermatitis, andautoeczematization, and statis dermatitis, hidradenitis suppurativa,psoriasis including plaqure psoriasis, nail psoriasis, guttatepsoriasis, scalp psoriasis, inverse psoriasis, pustular psoriasis, anderythrodermis psoriasis, rosacea and scleroderma including morphea.

Another type of autoimmune disorder is a gastrointestinal disorder. Agastrointestinal disorder includes, without limitation, irritable boweldisease, an inflammatory bowel disease including Crohn's disease and anulcerative colitis like ulcerative proctitis, left-sided colitis,pancolitis and fulminant colitis.

Aspects of the present invention provide, in part, a transplantrejection. Transplant rejection occurs when a transplanted organ ortissue is not accepted by the body of the transplant recipient becausethe immune system of the recipient attacks the transplanted organ ortissue. An adaptive immune response, transplant rejection is mediatedthrough both T cell mediated and humoral immune (antibodies) mechanisms.The number of mismatched alleles determines the speed and magnitude ofthe rejection response. Different mechanisms tend to act againstdifferent transplants.

A transplant rejection can be classified as a hyperacute rejection, anacute rejection, or a chronic rejection. Hyperacute rejection is acomplement-mediated response in recipients with pre-existing antibodiesto the donor (for example, ABO blood type antibodies). Hyperacuterejection occurs within minutes after the transplant and must beimmediately removed to prevent a severe systemic inflammatory response.Rapid agglutination of the blood occurs.

Acute rejection may begin as early as one week after transplantation (asopposed to hyperacute rejection, which is immediate). The risk of acuterejection is highest in the first three months after transplantation.However, acute rejection can also occur months to years aftertransplantation. The reason that acute rejection usually begins one weekafter transplantation is that T-cells are involved in the rejectionmechanism. These T-cells must differentiate before rejection begins. TheT-cells cause cells in the transplanted tissue to lyse, or producecytokines that cause necrosis of the transplanted tissue. A singleepisode of acute rejection is not a cause for concern if recognized andtreated promptly, and rarely leads to organ failure. Acute rejectionoccurs to some degree in all transplants (except those between identicaltwins) unless the immune response in altered through the use ofimmunosuppressive drugs. It is caused by mismatched HLA, which arepresent on all cells of the body. There are a large number of differentalleles of each HLA, so a perfect match between all HLA in the donortissue and the recipient's body is extremely rare.

Chronic rejection of a transplanted organ or tissue is where therejection is due to a poorly understood chronic inflammatory and immuneresponse against the transplanted tissue. Chronic rejection after lungtransplantation is the leading cause of long-term morbidity andmortality in lung transplant patients

Also included in the term “transplant rejection” is a graft-versus-hostdisease (GVHD). GVHD is a common complication of allogeneic bone marrowtransplantation in which functional immune cells in the transplantedmarrow recognize the recipient as “foreign” and mount an immunologicattack. It can also take place in a blood transfusion under certaincircumstances. GVHD is divided into acute and chronic forms. The acuteor fulminant form of the disease (aGVHD) is normally observed within thefirst 100 days post-transplant,[2] and is a major challenge totransplants owing to associated morbidity and mortality. The chronicform of graft-versus-host-disease (cGVHD) normally occurs after 100days. The appearance of moderate to severe cases of cGVHD adverselyinfluences long-term survival. Acute and chronic GVHD appear to involvedifferent immune cell subsets, different cytokine profiles, somewhatdifferent host targets, and respond differently to treatment.

Acute GVHD is characterized by selective damage to the liver, skin andmucosa, gastrointestinal tract, immune system (the hematopoietic system,e.g., the bone marrow and the thymus) itself, and the lungs in the formof idiopathic pneumonitis. Acute GVHD of the GI tract can result insevere intestinal inflammation, sloughing of the mucosal membrane,severe diarrhea, abdominal pain, nausea, and vomiting. This is typicallydiagnosed via intestinal biopsy. Liver GVHD is measured by the bilirubinlevel in acute patients. Skin GVHD results in a diffuse maculopapularrash, sometimes in a lacy pattern. Acute GVHD is staged as follows:overall grade (skin-liver-gut) with each organ staged individually froma low of 1 to a high of 4. Patients with grade IV GVHD usually have apoor prognosis. If the GVHD is severe and requires intenseimmunosuppression involving steroids and additional agents to get undercontrol, the patient may develop severe infections as a result of theimmunosuppression and may die of infection. Chronic GVHD also attacksthe above organs, but over its long-term course can also cause damage tothe connective tissue and exocrine glands.

Aspects of the present invention provide, in part, reducing a symptomassociated with an autoimmune disorder or transplant rejection. Theactual symptoms associated with an autoimmune disorder or transplantrejection disclosed herein are well known and can be determined by aperson of ordinary skill in the art by taking into account factors,including, without limitation, the location of the autoimmune disorderor transplant rejection, the cause of the autoimmune disorder ortransplant rejection, the severity of the autoimmune disorder ortransplant rejection, the tissue or organ affected by the autoimmunedisorder or transplant rejection, and the autoimmune disorder ortransplant rejection associated with the inflammation. Non-limitingexamples of a symptom reduced by a method of treating an autoimmunedisorder or transplant rejection disclosed herein include inflammation,fatigue, dizziness, malaise, elevated fever and high body temperature,extreme sensitivity to cold in the hands and feet, weakness andstiffness in muscles and joints, weight changes, digestive orgastrointestinal problems, low or high blood pressure, irritability,anxiety, or depression, infertility or reduced sex drive (low libido),blood sugar changes, and depending on the type of autoimmune disorder ortransplant rejection, an increase in the size of an organ or tissue, orthe destruction of an organ or tissue. Non-limiting examples of aninflammation symptom reduced by a method of treating an autoimmunedisorder disclosed herein include edema, hyperemia, erythema, bruising,tenderness, stiffness, swollenness, fever, a chill, congestion of therespiratory tract including nose and/or bronchi, congestion of a sinus,a breathing problem, fluid retention, a blood clot, a loss of appetite,an increased heart rate, a formation of granulomas, fibrinous, pus, ornon-viscous serous fluid, a formation of an ulcer, or pain.

Aspects of the present invention provide, in part, a mammal. A mammalincludes a human, and a human can be a patient. Other aspects of thepresent invention provide, in part, an individual. An individualincludes a mammal and a human, and a human can be a patient.

Aspects of the present invention provide, in part, administering acompound or a composition disclosed herein. As used herein, the term“administering” means any delivery mechanism that provides a compound ora composition disclosed herein to an individual that potentially resultsin a clinically, therapeutically, or experimentally beneficial result.

Administration of a compound or a composition disclosed herein include avariety of enteral or parenteral approaches including, withoutlimitation, oral administration in any acceptable form, such as, e.g.,tablet, liquid, capsule, powder, or the like; topical administration inany acceptable form, such as, e.g., drops, spray, creams, gels orointments; buccal, nasal, and/or inhalation administration in anyacceptable form; rectal administration in any acceptable form; vaginaladministration in any acceptable form; intravascular administration inany acceptable form, such as, e.g., intravenous bolus injection,intravenous infusion, intra-arterial bolus injection, intra-arterialinfusion and catheter instillation into the vasculature; peri- andintra-tissue administration in any acceptable form, such as, e.g.,intraperitoneal injection, intramuscular injection, subcutaneousinjection, subcutaneous infusion, intraocular injection, retinalinjection, or sub-retinal injection or epidural injection;intravesicular administration in any acceptable form, such as, e.g.,catheter instillation; and by placement device, such as, e.g., animplant, a stent, a patch, a pellet, a catheter, an osmotic pump, asuppository, a bioerodible delivery system, a non-bioerodible deliverysystem or another implanted extended or slow release system. Anexemplary list of biodegradable polymers and methods of use aredescribed in, e.g., Handbook of Biodegradable Polymers (Abraham J. Dombet al., eds., Overseas Publishers Association, 1997).

A compound or a composition disclosed herein can be administered to amammal using a variety of routes. Routes of administration suitable fortreating an autoimmune disorder or transplant rejection as disclosedherein include both local and systemic administration. Localadministration results in significantly more delivery of a compositionto a specific location as compared to the entire body of the mammal,whereas, systemic administration results in delivery of a composition toessentially the entire body of the individual. Routes of administrationsuitable for or treating an autoimmune disorder or transplant rejectionas disclosed herein also include both central and peripheraladministration. Central administration results in delivery of a compoundor a composition to essentially the central nervous system of theindividual and includes, e.g., intrathecal administration, epiduraladministration as well as a cranial injection or implant. Peripheraladministration results in delivery of a compound or a composition toessentially any area of an individual outside of the central nervoussystem and encompasses any route of administration other than directadministration to the spine or brain. The actual route of administrationof a compound or a composition disclosed herein used can be determinedby a person of ordinary skill in the art by taking into account factors,including, without limitation, the type of an autoimmune disorder ortransplant rejection, the location of the autoimmune disorder ortransplant rejection, the cause of the autoimmune disorder or transplantrejection, the severity of the autoimmune disorder or transplantrejection, the duration of treatment desired, the degree of reliefdesired, the duration of relief desired, the particular compound orcomposition used, the rate of excretion of the compound or compositionused, the pharmacodynamics of the compound or composition used, thenature of the other compounds to be included in the composition, theparticular route of administration, the particular characteristics,history and risk factors of the individual, such as, e.g., age, weight,general health and the like, the response of the individual to thetreatment, or any combination thereof. An effective dosage amount of acompound or a composition disclosed herein can thus readily bedetermined by the person of ordinary skill in the art considering allcriteria and utilizing his best judgment on the individual's behalf.

In an embodiment, a compound or a composition disclosed herein isadministered systemically to a mammal. In another embodiment, a compoundor a composition disclosed herein is administered locally to a mammal.In an aspect of this embodiment, a compound or a composition disclosedherein is administered to a site of autoimmune disorder or transplantrejection of a mammal. In another aspect of this embodiment, a compoundor a composition disclosed herein is administered to the areasurrounding an autoimmune disorder or transplant rejection of a mammal.

Aspects of the present specification provide, in part, administering atherapeutically effective amount of a compound or a compositiondisclosed herein. As used herein, the term “therapeutically effectiveamount” is synonymous with “therapeutically effective dose” and whenused in reference to treating an autoimmune disorder means the minimumdose of a compound or composition disclosed herein necessary to achievethe desired therapeutic effect and includes a dose sufficient to reducea symptom associated with an autoimmune disorder or transplantrejection. In aspects of this embodiment, a therapeutically effectiveamount of a compound or a composition disclosed herein reduces a symptomassociated with an autoimmune disorder or transplant rejection by, e.g.,at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90% or at least 100%. Inother aspects of this embodiment, a therapeutically effective amount ofa compound or a composition disclosed herein reduces a symptomassociated with an autoimmune disorder or transplant rejection by, e.g.,at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most60%, at most 70%, at most 80%, at most 90% or at most 100%. In yet otheraspects of this embodiment, a therapeutically effective amount of acompound or a composition disclosed herein reduces a symptom associatedwith an autoimmune disorder or transplant rejection by, e.g., about 10%to about 100%, about 10% to about 90%, about 10% to about 80%, about 10%to about 70%, about 10% to about 60%, about 10% to about 50%, about 10%to about 40%, about 20% to about 100%, about 20% to about 90%, about 20%to about 80%, about 20% to about 20%, about 20% to about 60%, about 20%to about 50%, about 20% to about 40%, about 30% to about 100%, about 30%to about 90%, about 30% to about 80%, about 30% to about 70%, about 30%to about 60%, or about 30% to about 50%. In still other aspects of thisembodiment, a therapeutically effective amount of a compound or acomposition disclosed herein is the dosage sufficient to reduces asymptom associated with an autoimmune disorder or transplant rejectionfor, e.g., at least one week, at least one month, at least two months,at least three months, at least four months, at least five months, atleast six months, at least seven months, at least eight months, at leastnine months, at least ten months, at least eleven months, or at leasttwelve months.

The amount of active component in a compound or a composition disclosedherein for treating an autoimmune disorder or transplant rejection canbe varied so that a suitable dosage is obtained. The actualtherapeutically effective amount of a compound or a compositiondisclosed herein to be administered to a mammal can be determined by aperson of ordinary skill in the art by taking into account factors,including, without limitation, the type of the autoimmune disorder ortransplant rejection, the location of the autoimmune disorder ortransplant rejection, the cause of the autoimmune disorder or transplantrejection, the severity of the autoimmune disorder or transplantrejection, the duration of treatment desired, the degree of reliefdesired, the duration of relief desired, the particular compound orcomposition used, the rate of excretion of the compound or compositionused, the pharmacodynamics of the compound or composition used, thenature of the other compounds to be included in the composition, theparticular route of administration, the particular characteristics,history and risk factors of the individual, such as, e.g., age, weight,general health and the like, the response of the individual to thetreatment, or any combination thereof. An effective dosage amount of acompound or a composition disclosed herein can thus readily bedetermined by the person of ordinary skill in the art considering allcriteria and utilizing his best judgment on the individual's behalf.

Additionally, where repeated administration of a compound or acomposition disclosed herein is used, the actual effect amount of acompound or a composition disclosed herein will further depend uponfactors, including, without limitation, the frequency of administration,the half-life of the compound or composition disclosed herein, or anycombination thereof. In is known by a person of ordinary skill in theart that an effective amount of a compound or a composition disclosedherein can be extrapolated from in vitro assays and in vivoadministration studies using animal models prior to administration tohumans. Wide variations in the necessary effective amount are to beexpected in view of the differing efficiencies of the various routes ofadministration. For instance, oral administration generally would beexpected to require higher dosage levels than administration byintravenous or intravitreal injection. Variations in these dosage levelscan be adjusted using standard empirical routines of optimization, whichare well-known to a person of ordinary skill in the art. The precisetherapeutically effective dosage levels and patterns are preferablydetermined by the attending physician in consideration of theabove-identified factors.

As a non-limiting example, when administering a compound or acomposition disclosed herein to a mammal, a therapeutically effectiveamount generally is in the range of about 0.001 mg/kg/day to about 100.0mg/kg/day. In aspects of this embodiment, an effective amount of acompound or a composition disclosed herein can be, e.g., about 0.01mg/kg/day to about 0.1 mg/kg/day, about 0.03 mg/kg/day to about 3.0mg/kg/day, about 0.1 mg/kg/day to about 3.0 mg/kg/day, or about 0.3mg/kg/day to about 3.0 mg/kg/day. In yet other aspects of thisembodiment, a therapeutically effective amount of a compound or acomposition disclosed herein can be, e.g., at least 0.001 mg/kg/day, atleast 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, atleast 10 mg/kg/day, or at least 100 mg/kg/day. In yet other aspects ofthis embodiment, a therapeutically effective amount of a compound or acomposition disclosed herein can be, e.g., at most 0.001 mg/kg/day, atmost 0.01 mg/kg/day, at most 0.1 mg/kg/day, at most 1.0 mg/kg/day, atmost 10 mg/kg/day, or at most 100 mg/kg/day.

As another non-limiting example, when administering a compound or acomposition disclosed herein to a mammal, a therapeutically effectiveamount generally is in the range of about 0.001 mg/m²/day to about 100.0mg/m²/day. In aspects of this embodiment, an effective amount of acompound or a composition disclosed herein can be, e.g., about 0.01mg/m²/day to about 0.1 mg/m²/day, about 0.03 mg/m²/day to about 3.0mg/m²/day, about 0.1 mg/m²/day to about 3.0 mg/m²/day, or about 0.3mg/m²/day to about 3.0 mg/m²/day. In yet other aspects of thisembodiment, a therapeutically effective amount of a compound or acomposition disclosed herein can be, e.g., at least 0.001 mg/m²/day, atleast 0.01 mg/m²/day, at least 0.1 mg/m²/day, at least 1.0 mg/m²/day, atleast 10 mg/m²/day, or at least 100 mg/m²/day. In yet other aspects ofthis embodiment, a therapeutically effective amount of a compound or acomposition disclosed herein can be, e.g., at most 0.001 mg/m²/day, atmost 0.01 mg/m²/day, at most 0.1 mg/m²/day, at most 1.0 mg/m²/day, atmost 10 mg/m²/day, or at most 100 mg/m²/day.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. For instance, treatment ofan autoimmune disorder or transplant rejection may comprise a one-timeadministration of an effective dose of a compound or a compositiondisclosed herein. As a non-limiting example, an effective dose of acompound or a composition disclosed herein can be administered once to amammal, e.g., as a single injection or deposition at or near the siteexhibiting a symptom of an autoimmune disorder or transplant rejectionor a single oral administration of the compound or a composition.Alternatively, treatment of an autoimmune disorder or transplantrejection may comprise multiple administrations of an effective dose ofa compound or a composition disclosed herein carried out over a range oftime periods, such as, e.g., daily, once every few days, weekly, monthlyor yearly. As a non-limiting example, a compound or a compositiondisclosed herein can be administered once or twice weekly to a mammal.The timing of administration can vary from mammal to mammal, dependingupon such factors as the severity of a mammal's symptoms. For example,an effective dose of a compound or a composition disclosed herein can beadministered to a mammal once a month for an indefinite period of time,or until the mammal no longer requires therapy. A person of ordinaryskill in the art will recognize that the condition of the mammal can bemonitored throughout the course of treatment and that the effectiveamount of a compound or a composition disclosed herein that isadministered can be adjusted accordingly.

A compound or a composition disclosed herein as disclosed herein canalso be administered to a mammal in combination with other therapeuticcompounds to increase the overall therapeutic effect of the treatment.The use of multiple compounds to treat an indication can increase thebeneficial effects while reducing the presence of side effects.

Aspects of the present specification may also be described as follows:

-   1. A method of treating an autoimmune disorder, the method    comprising the step of administering to an individual in need    thereof a therapeutically effective amount of a RXR agonist, wherein    administration of the RXR agonist reduces a symptom associated with    the autoimmune disorder, thereby treating the individual.-   2. A method of treating inflammation as a result of an autoimmune    disorder, the method comprising the step of administering to an    individual in need thereof a therapeutically effective amount of a    RXR agonist, wherein administration of the compound or composition    reduces a symptom associated with inflammation, thereby treating the    individual.-   3. A method of treating a transplant rejection, the method    comprising the step of administering to an individual in need    thereof a therapeutically effective amount of a RXR agonist, wherein    administration of the RXR agonist reduces a symptom associated with    the transplant rejection, thereby treating the individual.-   4. Use of a RXR agonist in the manufacture of a medicament in the    treatment of an autoimmune disorder, an inflammation as a result of    an autoimmune disorder, and/or a transplant rejection.-   5. Use of a RXR agonist to treat an autoimmune disorder, an    inflammation as a result of an autoimmune disorder, or a transplant    rejection, wherein administration of the RXR agonist reduces a    symptom associated with the autoimmune disorder or transplant    rejection, thereby treating the individual.-   6. The method or use according to any one of embodiments 1-5,    wherein the RXR agonist is a compound having the structure of    formula I:

-   -   wherein Z is a radical shown in Formula II:

-   -   Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally        substituted with one or two R⁴ groups, or Y is selected from        phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl,        pyrimidiyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the        groups being optionally substituted with one or two R⁴ groups,        the divalent Y radical being substituted by the Z and        —(CR¹═CR¹=CR¹═CR¹)— groups on adjacent carbons; R¹ and R²        independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen,        lower alkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or        halogen, and B is hydrogen, —COOH or a pharmaceutically        acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹,        —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O, —OCOR⁷, —CR⁷(OR¹²)₂,        —CR⁷OR¹³O, or tri-lower alkylsilyl, where R⁷ is an alkyl,        cycloalkyl or alkenyl group, containing 1 to 5 carbons, R⁸ is an        alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10        carbons or trimethylsilylalkyl where the alkyl group has 1 to 10        carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰        independently are hydrogen, an alkyl group of 1 to 10 carbons,        or a cycloalkyl group of 5-10 carbons, or phenyl or lower        alkylphenyl, R¹¹ is lower alkyl, phenyl or lower alkylphenyl,        R¹² is lower alkyl, and R¹³ is divalent alkyl radical of 2-5        carbons; and n is 1 or 2.

-   7. The method or use according to any one of embodiments 1-5,    wherein the RXR agonist is a compound having the structure of    formula I:

-   -   wherein Z is a radical shown in Formula II:

-   -   Y is selected from thienyl and furyl, the groups being        optionally with one or two R⁴ groups, the divalent Y radical        being substituted by the Z and —(CR¹═CR¹=CR¹═CR¹)— groups on        adjacent carbons; R¹ and R² independently are H, lower alkyl or        fluoroalkyl; R³ is hydrogen, lower alkyl, Cl or Br; R⁴ is lower        alkyl, fluoroalkyl or halogen, and B is hydrogen, —COOH or a        pharmaceutically acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰,        —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O,        —OCOR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or tri-lower alkylsilyl, where        R⁷ is an alkyl, cycloalkyl or alkenyl group, containing 1 to 5        carbons, R⁸ is an alkyl group of 1 to 10 carbons, a cycloalkyl        group of 5 to 10 carbons or trimethylsilylalkyl where the alkyl        group has 1 to 10 carbons, or R⁸ is phenyl or lower alkylphenyl,        R⁹ and R¹⁰ carbons, or a cycloalkyl groups of 5-10 carbons, or        phenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or lower        alkylphenyl, R¹² is lower alkyl, and R¹³ is divalent alkyl        radical of 2-5 carbons; and n is 1 or 2.

-   8. The method or use according to any one of embodiments 1-7,    wherein the RXR agonist is a compound having the structure of    formula III:

-   -   wherein R² is hydrogen or lower alkyl; R³ is hydrogen or lower        alkyl, and B is hydrogen, COOH or a pharmaceutically acceptable        salt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹,        —CHO, —CH(OR¹²)₂, —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or        tri-lower alkylsilyl, where R⁷ is an alkyl, cycloalkyl or        alkenyl group containing 1 to 5 carbons, R⁸ is an alkyl group of        1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons or        trimethylsilylalkyl where the alkyl group has 1 to 10 carbons,        or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰ independently        are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl        group of 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ is        lower alkyl, phenyl or lower alkylphenyl, R¹² is lower alkyl,        and R¹³ is divalent alkyl radical of 2-5 carbons.

-   9. The method or use according to any one of embodiments 1-8,    wherein the RXR agonist is a compound having the structure of    formula IV:

-   -   wherein n is 1 or 2; R¹ and R² independently are H, lower alkyl        or fluoroalkyl; R³ is hydrogen, lower alkyl, Cl or Br; R⁴ is H,        lower alkyl, fluoroalkyl or halogen, and B is hydrogen, —COOH or        a pharmaceutically acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰,        —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O, —COR⁷,        —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or trilower alkylsilyl where R⁷ is an        alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R⁸        is an alkyl group of 1 to 10 carbons, or R⁸ is phenyl or lower        alkylphenyl, R⁹ and R¹⁰ independently are hydrogen, an alkyl        group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,        or phenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or        lower alkylphenyl, R¹² is lower alkyl, and R¹³ is divalent alkyl        radical of 2-5 carbons.

-   10. The method or use according to any one of embodiments 1-9,    wherein the RXR agonist is a compound having the structure of    formula V:

-   -   where R⁴ is lower alkyl of 1 to 6 carbons; B is —COOH or —COOR⁸        where R⁸ is lower alkyl of 1 to 6 carbons, and the configuration        about the cyclopropane ring is cis, and the configuration about        the double bonds in the pentadienoic acid or ester chain        attached to the cyclopropane ring is trans in each of the double        bonds, or a pharmaceutically acceptable salt of the compound.

-   11. The method or use according to any one of embodiments 1-10,    wherein the RXR agonist is a compound having the structure of    formula VI:

-   -   wherein Z is a radical shown in Formula VII:

-   -   Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally        substituted with one or two R⁴ groups, or Y is selected from        phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyridazinyl,        pyrimidiyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the        groups being optionally substituted with one or two R⁴ groups,        the divalent Y radical being substituted by the Z and        —(CR¹═CR¹=CR¹═CR¹)— groups on adjacent carbons; X is S or O; R¹        and R² independently are H, lower alkyl or fluoroalkyl; R³ is        hydrogen, lower alkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl        or halogen, and B is hydrogen, —COOH or a pharmaceutically        acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹,        —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O, —OCOR⁷, —CR⁷(OR¹²)₂,        —CR⁷OR¹³O, or tri-lower alkylsilyl, where R⁷ is an alkyl,        cycloalkyl or alkenyl group, containing 1 to 5 carbons, R⁸ is an        alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10        carbons or trimethylsilylalkyl where the alkyl group has 1 to 10        carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰        independently are hydrogen, an alkyl group of 1 to 10 carbons,        or a cycloalkyl group of 5-10 carbons, or phenyl or lower        alkylphenyl, R¹¹ is lower alkyl, phenyl or lower alkylphenyl,        R¹² is lower alkyl, and R¹³ is divalent alkyl radical of 2-5        carbons.

-   12. The method or use according to any one of embodiments 1-11,    wherein the RXR agonist is a compound having the structure of    formula VIII:

-   -   wherein X is S or O; R² is hydrogen or lower alkyl; R³ is        hydrogen or lower alkyl, and B is hydrogen, —COOH or a        pharmaceutically acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰,        —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O, —COR⁷,        —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or trilower alkylsilyl, where R⁷ is an        alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R⁸        is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to        10 carbons or trimethylsilylalkyl where the alkyl group has 1 to        10 carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰        independently are hydrogen, an alkyl group of 1 to 10 carbons,        or a cycloalkyl group of 5-10 carbons, or phenyl or lower        alkylphenyl, R¹¹ is lower alkyl, phenyl or lower alkylphenyl,        R¹² is lower alkyl, and R¹³ is divalent alkyl radical of 2-5        carbons.

-   13. The method or use according to any one of embodiments 1-12,    wherein the RXR agonist is a compound having the structure of    formula IX:

-   -   wherein Z is a radical shown in Formula X:

-   -   Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl,        pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being        optionally substituted with one or two R⁴ groups, the divalent Y        radical being substituted by the Z and —(CR¹═CR¹=CR¹═CR¹)—        groups on adjacent carbons; X is NR⁵; n is 1 or 2; R¹ and R²        independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen,        lower alkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or        halogen; R⁵ is H or lower alkyl, and B is hydrogen, —COOH or a        pharmaceutically acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰,        —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O, —COR⁷,        —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or trilower alkylsilyl, where R⁷ is an        alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R⁸        is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to        10 carbons or trimethylsilylalkyl where the alkyl group has 1 to        10 carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰        independently are hydrogen, an alkyl group of 1 to 10 carbons,        or a cycloalkyl group of 5-10 carbons, or phenyl or lower        alkylphenyl, R¹¹ is lower alkyl, phenyl or lower alkylphenyl,        R¹² is lower alkyl, and R¹³ is divalent alkyl radical of 2 to 5        carbons.

-   14. The method or use according to any one of embodiments 1-13,    wherein the RXR agonist is a compound having the structure of    formula IX:

-   -   wherein Z is a radical shown in Formula XI:

-   -   Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl,        pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups being        optionally substituted with one or two R⁴ groups, the divalent Y        radical being substituted by the Z and —(CR¹═CR¹=CR¹═CR¹)—        groups on adjacent carbons; X is NR⁵; n is 1 or 2; R¹ and R²        independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen,        lower alkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or        halogen; R⁵ is H or lower alkyl, and B is hydrogen, —COOH or a        pharmaceutically acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰,        —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O, —COR⁷,        —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or trilower alkylsilyl, where R⁷ is an        alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R⁸        is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to        10 carbons or trimethylsilylalkyl where the alkyl group has 1 to        10 carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰        independently are hydrogen, an alkyl group of 1 to 10 carbons,        or a cycloalkyl group of 5-10 carbons, or phenyl or lower        alkylphenyl, R¹¹ is lower alkyl, phenyl or lower alkylphenyl,        R¹² is lower alkyl, and R¹³ is divalent alkyl radical of 2 to 5        carbons.

-   15. The method or use according to any one of embodiments 1-14,    wherein the RXR agonist is a compound having the structure of    formula XII:

-   -   wherein R is H, lower alkyl or 1 to 6 carbons, or a        pharmaceutically acceptable salt of the compound.

-   16. The method or use according to any one of embodiments 1-5,    wherein the RXR agonist is a compound having the structure of    formula XII:

-   -   wherein Z is a radical shown in Formula XIV:

-   -   Y is cyclopropyl, the Y group being optionally substituted with        one or two R⁴ groups, the divalent Y radical being substituted        by the Z and —(CR¹═CR¹=CR¹═CR¹)— groups on adjacent carbons; X        is NR⁵; R¹ and R² independently are H, lower alkyl or        fluoroalkyl; R³ is hydrogen, lower alkyl, Cl or Br; R⁴ is lower        alkyl, fluoroalkyl or hydrogen; R⁵ is H or lower alkyl, and B is        hydrogen, —COOH or a pharmaceutically acceptable salt thereof,        —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO,        —CH(OR¹²)₂, —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or trilower        alkylsilyl, where R⁷ is an alkyl, cycloalkyl or alkenyl group        containing 1 to 5 carbons, R⁸ is an alkyl group of 1 to 10        carbons, a cycloalkyl group of 5 to 10 carbons or        trimethylsilylalkyl where the alkyl group has 1 to 10 carbons,        or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰ independently        are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl        group of 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ is        lower alkyl, phenyl or lower alkylphenyl, R¹² is lower alkyl,        and R¹³ is divalent alkyl radical of 2 to 5 carbons.

-   17. The method or use according to any one of embodiments 1-16,    wherein the RXR agonist is a compound having the structure of    formula XV:

-   -   wherein X is NR⁵; R⁵ is H or lower alkyl; R² is H or lower        alkyl; R³ is H or lower alkyl, and B is hydrogen, —COOH or a        pharmaceutically acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰,        —CH₂OH, —CH₂OR¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O, —COR⁷,        —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or trilower alkylsilyl, where R⁷ is an        alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R⁸        is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to        10 carbons or trimethylsilylalkyl where the alkyl group has 1 to        10 carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰        independently are hydrogen, an alkyl group of 1 to 10 carbons,        or a cycloalkyl group of 5-10 carbons, or phenyl or lower        alkylphenyl, R¹¹ is lower alkyl, phenyl or lower alkylphenyl,        R¹² is lower alkyl, and R¹³ is divalent alkyl radical of 2 to 5        carbons.

-   18. The method or use according to any one of embodiments 1-17,    wherein the RXR agonist is a compound having the structure of    formula XVI:

-   -   where Y is a bivalent radical having Formula XVII:

-   -   the two X¹ groups jointly represent an oxo (═O) or thione (═S)        function, or X¹ is independently selected from H or alkyl of 1        to 6 carbons; the two X² groups jointly represent an oxo (═O) or        a thione (═S) function, or X² independently selected from H or        alkyl of 1 to 6 carbons, with the proviso that one of the joint        X¹ grouping or of the joint X² grouping represents an oxo (═O)        or thione (═S) function; W is O, C(R¹)₂, or W does not exist; R¹        is independently H, lower alkyl of 1 to 6 carbons, or lower        fluoroalkyl of 1 to 6 carbons; R² is independently H, lower        alkyl of 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons;        R³ is hydrogen, lower alkyl of 1 to 6 carbons, OR¹, fluoro        substituted lower alkyl of 1 to 6 carbons halogen, NO₂, NH₂,        —NHCO(C₁-C₆) alkyl, or —NHCO(C₁-C₆) alkenyl; A is hydrogen,        —COOH or a pharmaceutically acceptable salt thereof, —COOR⁸,        —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂,        —CH(OR¹³O), —COR⁷, —CR⁷(OR¹²)₂, —CR⁷(OR¹³O), or —Si(C₁-C₆)₃,        where R⁷ is an alkyl, cycloalkyl or alkenyl group containing 1        to 5 carbons, R⁸ is an alkyl group of 1 to 10 carbons or        (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons,        or a cycloalkyl group of 5 to 10 carbons, or R⁸ is phenyl or        lower alkyphenyl, R⁹ and R¹⁰ independently are hydrogen, an        alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10        carbons, or phenyl, hydroxyphenyl or lower alkylphenyl, R¹¹ is        lower alkyl, phenyl or lower alkylphenyl, R¹² is lower alkyl,        and R¹³ is divalent alkyl radical of 2 to 5 carbons, and R¹⁴ is        H, alkyl of 1 to 10 carbons, fluoro-substituted alkyl of 1 to 10        carbons, alkenyl of 2 to 10 carbons and having 1 to 3 double        bonds.

-   19. The method or use according to any one of embodiments 1-18,    wherein the RXR agonist is a compound having the structure of    formula XVIII:

-   -   wherein R¹ is independently H, lower alkyl of 1 to 6 carbons, or        lower fluoroalkyl of 1 to 6 carbons; R¹* is hydrogen or        C₁₋₆-alkyl; R²* is independently H, lower alkyl of 1 to 6        carbons, or lower fluoroalkyl of 1 to 6 carbons; R³* is        hydrogen, lower alkyl of 1 to 6 carbons, fluoro substituted        lower alkyl of 1 to 6 carbons or halogen; X¹* is an oxo (═O) or        a thione (═S) group; A* is hydrogen, —COOH or a pharmaceutically        acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, where R⁸ is an alkyl        group of 1 to 10 carbons or (trimethylsilyl)alkyl where the        alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to        10 carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰        independently are hydrogen, an alkyl group of 1 to 10 carbons,        or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl        or lower alkylphenyl, and the cyclopropyl group is attached to        the 6 or 7 position of the tetrahydroquinoline moiety, and R¹⁴*        is alkyl of 1 to 10 carbons or fluoro-substituted alkyl of 1 to        10 carbons.

-   20. The method or use according to any one of embodiments 1-19,    wherein the RXR agonist is a compound having the structure of    formulae XIX, XX, or XXI:

-   -   where X is O, S, or (CR¹R¹)_(n) where n is 0, 1 or 2; Y is a        bivalent radical having Formulae XXII or XXIII where o is an        integer between 1 through 4

-   -   or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical        having 1 to 3 heteroatoms selected from N, S and O, the aryl or        heteroaryl groups being unsubstituted, or substituted with 1 to        3 C₁₋₆ alkyl or with 1 to 3 C₁₋₆fluoroalkyl groups with the        proviso that when the compound is in accordance with Formula II        then Y is not a 5 or 6 membered ring; X¹ is S or NH; R¹ is        independently H, lower alkyl of 1 to 6 carbons, or lower        fluoroalkyl of 1 to 6 carbons; R² is independently H, lower        alkyl of 1 to 6 carbons, OR¹, adamantly, or lower fluoroalkyl of        1 to 6 carbons, or the two R² groups jointly represent an oxo        (═O) group with the proviso that when the compound is in        accordance with Formula II then at least one of the R²        substituents is branched-chain alkyl or adamantly; R³ is        hydrogen, lower alkyl of 1 to 6 carbons, OR¹, fluoro substituted        lower alkyl of 1 to 6 carbons or halogen, NO₂, NH₂, —NHCO(C₁-C₆)        alkyl, or —NHCO(C₁-C₆) alkenyl; A is —COOH or a pharmaceutically        acceptable salt thereof, COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹,        —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CH(OR¹³O), —COR⁷, —CR⁷(OR¹²)₂,        —CR⁷(OR¹³O), or —Si(C₁₋₆alkyl)₃, where R⁷ is an alkyl,        cycloalkyl or alkenyl group containing 1 to 5 carbons, R⁸ is an        alkyl group of 1 to 10 carbons or (trimethylsilyl) alkyl where        the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5        to 10 carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰        independently are hydrogen, an alkyl group of 1 to 10 carbons,        or a cycloalkyl group of 5-10 carbons, or phenyl, hydroxyphenyl        or lower alkylphenyl, R¹² is lower alkyl, and R¹³ is divalent        alkyl radical of 2-5 carbons, and R¹⁴ is alkyl of 1 to 10        carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of        2 to 10 carbons and having 1 to 3 double bonds, alkynyl having 2        to 10 carbons and 1 to 3 triple bonds, carbocyclic aryl selected        from the group consisting of phenyl, C₁-C₁₀-alkylphenyl,        naphthyl, C₁-C₁₀-alkylnaphthyl, phenyl-C₁-C₁₀-alkyl,        naphthyl-C₁-C₁₀ alkyl, C₁-C₁₀-alkenylphenyl having 1 to 3 double        bonds, C₁-C₁₀-alkynylphenyl having 1 to 3 triple bonds,        phenyl-C₁-C₁₀ alkenyl having 1 to 3 double bonds, phenyl-C₁-C₁₀        alkenyl having 1 to 3 triple bonds, hydroxyl alkyl of 1 to 10        carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3 double        bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triple        bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2        to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to        10 carbons and 1 to 3 triple bonds, acyloxyalkyl of 1 to 10        carbons, acyloxyalkenyl having 2 to 10 carbons and 1 to 3 double        bonds, or acyloxyalkynyl of 2 to 10 carbons and 1 to 3 triple        bonds where the acyl group is represented by —COR⁸, or R¹⁴ is a        5 or 6 membered heteroaryl group having 1 to 3 heteroatoms, the        heteroatoms being selected from a group consisting of O, S, and        N, the heteroaryl group being unsubstituted or substituted with        a C₁-C₁₀ alkyl group, with a C₁-C₁₀ fluoroalkyl group, or with        halogen, and the dashed line in Formula XXII represents a bond        or absence of a bond.

-   21. The method or use according to any one of embodiments 1-20,    wherein the RXR agonist is a compound having the structure of    formula XXIV:

-   -   wherein R is H, lower alkyl of 1 to 6 carbons, or a        pharmaceutically acceptable salt of the compound.

-   22. The method or use according to any one of embodiments 1-21,    wherein the RXR agonist is a compound having the structure of    formula XXV:

-   -   wherein R is H, lower alkyl of 1 to 6 carbons, and R¹ is        iso-propyl or tertiary-butyl, or a pharmaceutically acceptable        salt of the compound.

-   23. The method or use according to any one of embodiments 1-22,    wherein the RXR agonist is a compound having the structure of    formula XXVI:

-   -   wherein R is H, lower alkyl of 1 to 6 carbons, and R¹ is        iso-propyl, n-butyl or tertiary-butyl, or a pharmaceutically        acceptable salt of the compound.

-   24. The method or use according to any one of embodiments 1-23,    wherein the RXR agonist is a compound having the structure of    formula XXVII:

-   -   where X is O or S; Y is a bivalent cycloalkyl or cycloalkenyl        radical optionally substituted with one to four R⁴ groups, the        cycloalkenyl radical having 5 to 6 carbons and one double bond,        or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical        having 1 to 3 heteroatoms selected from N, S and O, the aryl or        heteroaryl groups optionally substituted with 1 to 4 R⁴ groups        with the proviso that the cycloalkyl or the cycloalkenyl radical        is not substituted on the same carbon with the condensed cyclic        moiety and with the diene containing moiety; R¹ is independently        H, alkyl of 1 to 6 carbons, or fluoroalkyl of 1 to 6 carbons; R²        is independently H, alkyl of 1 to 8 carbons, or fluoroalkyl of 1        to 8 carbons; R¹² is independently H, alkyl of 1 to 8 carbons,        or fluoroalkyl of 1 to 8 carbons; R³ is hydrogen, alkyl of 1 to        10 carbons, fluoro substituted alkyl of 1 to 10 carbons,        halogen, alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10        carbons; NO₂, NH₂, —NHCO(C₁-C₆) alkyl, —NHCO(C₁-C₆) alkenyl,        —NR¹H or N(R¹)₂, benzyloxy, C₁-C₆ alkyl-substituted benzyloxy,        or R³ is selected from the groups shown below,

-   -   R⁴ is H, halogen, alkyl of 1 to 10 carbons, fluoro substituted        alkyl of 1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio        of 1 to 10 carbons; m is an integer having the values of 0 to 3;        r is an integer having the values of 1 to 10; s is an integer        having the values 1 to 4; t is an integer having the values 1 to        5;

-   -   represents a 5 or 6 membered heteroaryl ring having 1 to 3        heteroatoms selected from the group consisting of N, S and O; B        is hydrogen, COOH or a pharmaceutically acceptable salt thereof,        —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO,        —CH(OR¹²)₂, —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or trilower        alkylsilyl, where R⁷ is an alkyl, cycloalkyl or alkenyl group        containing 1 to 5 carbons, R⁸ is an alkyl group of 1 to 10        carbons, a cycloalkyl group of 5 to 10 carbons or        trimethylsilylalkyl where the alkyl group has 1 to 10 carbons,        or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰ independently        are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl        group of 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ is        lower alkyl, phenyl or lower alkylphenyl, R¹² is lower alkyl,        and R¹³ is divalent alkyl radical of 2 to 5 carbons.

-   25. The method or use according to any one of embodiments 1-24,    wherein the RXR agonist is a compound having the structure of    formula XXVIII:

-   -   wherein R¹ is H or methyl; R⁸ is H, alkyl of 1 to 6 carbons, or        a pharmaceutically acceptable cation, and R³ is hydrogen, alkyl        of 1 to 10 carbons, halogen, alkoxy of 1 to 10 carbons, or R³ is        selected from the groups shown below

-   -   where R⁴ is H, halogen, alkyl of 1 to 10 carbons, carbons,        alkoxy of 1 to 10; r is an integer having the values of 1 to 10;        s is an integer having the values 1 to 4;

-   -   represents a 5 or 6 membered heteroaryl ring having 1 to 3        heteroatoms selected from the group consisting of N, S and O,        and t is an integer having the values 1 to 5.

-   26. The method or use according to any one of embodiments 1-25,    wherein the RXR agonist is    3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)    heptadienoic acid, and has the structure of formula XXIX:

-   27. The method or use according to any one of embodiments 1, 2, or    4-26, wherein the autoimmune disorder is systemic autoimmune    disorder or organ-specific autoimmune disorder.-   28. The method or use according to any one of embodiments 1, 2, or    4-27, wherein the autoimmune disorder is an acute disseminated    encephalomyelitis (ADEM), an Addison's disease, an allergy, allergic    rhinitis, an Alzheimer's disease, an anti-phospholipid antibody    syndrome (APS), an arthritis, an asthma, an autoimmune deficiency    syndrome (AIDS), an autoimmune hemolytic anemia, an autoimmune    hepatitis, an autoimmune inner ear disease, a bullous pemphigoid, a    celiac disease, a Chagas disease, a chronic obstructive pulmonary    disease (COPD), a diabetes mellitus type 1 (IDDM), an endometriosis,    a gastrointestinal disorder, a Goodpasture's syndrome, a Graves'    disease, a Guillain-Barré syndrome (GBS), a Hashimoto's thyroiditis,    a hidradenitis suppurativa, an idiopathic thrombocytopenic purpura,    an interstitial cystitis, a lupus, a morphea, a multiple sclerosis    (MS), a myasthenia gravis, a myopathy such as, e.g., a    dermatomyositis, an inclusion body myositis, or a polymyositis, a    myositis, a narcolepsy, a neuromyotonia, a Parkinson's disease, a    pemphigus vulgaris, a pernicious anaemia, a primary biliary    cirrhosis, a psoriasis, a recurrent disseminated encephalomyelitis,    a rheumatic fever, a schizophrenia, a scleroderma, a Sjögren's    syndrome, a skin disorder, a tenosynovitis, a uveitis, a vasculitis,    or a vitiligo.-   29. The method or use according to embodiment 28, wherein the skin    disorder is a dermatitis, an eczema, a statis dermatitis, a    hidradenitis suppurativa, a psoriasis, a rosacea or a scleroderma.-   30. The method or use according to embodiment 29, wherein the eczema    is an atopic eczema, a contact eczema, a xerotic eczema, a    seborrhoeic dermatitis, a dyshidrosis, a discoid eczema, a venous    eczema, a dermatitis herpetiformis, a neurodermatitis, or an    autoeczematization.-   31. The method or use according to embodiment 29, wherein the    psoriasis is a plaqure psoriasis, a nail psoriasis, a guttate    psoriasis, a scalp psoriasis, an inverse psoriasis, a pustular    psoriasis, or an erythrodermis psoriasis.-   32. The method or use according to embodiment 28, wherein the    arthritis is a monoarthritis, an oligoarthritis, or a polyarthritis.-   33. The method or use according to embodiment 28, wherein the    arthritis is an auto-immune disease or a non-autoimmune disease.-   34. The method or use according to embodiment 28, wherein the    arthritis is an osteoarthritis, a rheumatoid arthritis, a juvenile    idiopathic arthritis, a septic arthritis, a spondyloarthropathy, a    gout, a pseudogout, or Still's disease-   35. The method or use according to embodiment 34, wherein the    spondyloarthropathy is an ankylosing spondylitis, a reactive    arthritis (Reiter's syndrome), a psoriatic arthritis, an    enteropathic arthritis associated with inflammatory bowel disease, a    Whipple disease or a Behcet disease.-   36. The method or use according to embodiment 28, wherein the    gastrointestinal disorder is an irritable bowel disease or an    inflammatory bowel.-   37. The method or use according to embodiment 36, wherein the    inflammatory bowel is a Crohn's disease or an ulcerative colitis.-   38. The method or use according to embodiment 28, wherein the lupus    is a discoid lupus erythematosus, a drug-induced lupus    erythematosus, a lupus nephritis, a neonatal lupus, a subacute    cutaneous lupus erythematosus, or a systemic lupus erythematosus.-   39. The method or use according to embodiment 28, wherein the    vasculitis is a Buerger's disease, a cerebral vasculitis, a    Churg-Strauss arteritis, a cryoglobulinemia, an essential    cryoglobulinemic vasculitis, a giant cell arteritis, a Golfer's    vasculitis, a Henoch-Schonlein purpura, a hypersensitivity    vasculitis, a Kawasaki disease, a microscopic    polyarteritis/polyangiitis, a polyarteritis nodosa, a polymyalgia    rheumatica (PMR), a rheumatoid vasculitis, a Takayasu arteritis, or    a Wegener's granulomatosis.-   40. The method or use according to any one of embodiments 3-26,    wherein the transplant rejection is a hyperacute rejection, an acute    rejection, or a chronic rejection.-   41. The method or use according to any one of embodiments 3-27,    wherein the transplant rejection is a graft-versus-host-disease.-   42. The method or use according to any one of embodiments 1-41,    wherein the therapeutically effective amount is about 0.01 mg/kg/day    to about 100 mg/kg/day.-   43. The method or use according to any one of embodiment 42, wherein    the therapeutically effective amount is about 0.1 mg/kg/day to about    10 mg/kg/day.-   44. The method or use according to any one of embodiments 1-41,    wherein the therapeutically effective amount is about 0.1 mg/m²/day    to about 100 mg/m²/day.-   45. The method or use according to embodiment 44, wherein the    therapeutically effective amount is about 15 mg/m²/day to about 60    mg/m²/day.-   46. The method or use according to any one of embodiment 1 or 3-45,    wherein the symptom reduced is inflammation, fatigue, dizziness,    malaise, elevated fever and high body temperature, extreme    sensitivity to cold in the hands and feet, weakness and stiffness in    muscles and joints, weight changes, digestive or gastrointestinal    problems, low or high blood pressure, irritability, anxiety, or    depression, infertility or reduced sex drive (low libido), blood    sugar changes, and depending on the type of autoimmune disorder or a    transplant rejection, an increase in the size of an organ or tissue,    or the destruction of an organ or tissue.-   47. The method or use according to embodiment 2 or 46, wherein the    inflammation symptom reduced is edema, hyperemia, erythema,    bruising, tenderness, stiffness, swollenness, fever, a chill,    congestion of the respiratory tract including nose and bronchi,    congestion of a sinus, a breathing problem, fluid retention, a blood    clot, a loss of appetite, an increased heart rate, a formation of    granulomas, fibrinous, pus, or non-viscous serous fluid, a formation    of an ulcer, or pain.-   48. The method or use according to any one of embodiments 1-47,    wherein the RXR agonist is a pure RXR agonist.-   49. The method or use according to embodiment 48, wherein the RXR    agonist is a pure RXR agonist that activates a permissive    heterodimer by 1% or less, 2% or less, 3% or less, 4% or less, 5% or    less, 6% or less, 7% or less, 8% or less, 9% or less, or 10% or less    relative to the ability of a non-pure RXR agonist to activate the    same permissive heterodimer.-   50. The method or use according to any one of embodiments 1-49,    wherein the RXR agonist has activity that promotes Treg cell    differentiation.-   51. The method or use according to embodiment 1-50, wherein the RXR    agonist promotes Treg cell differentiation by at least 10%, at least    20%, at least 30%, at least 40%, at least 50%, at least 60%, at    least 70%, at least 80%, at least 90%, at least 100%, at least 200%,    at least 300%, at least 400%, or at least 500%.-   52. The method or use according to any one of embodiments 1-51,    wherein the RXR agonist increases Foxp3 and/or α4β7 expression in    cells exposed to the RXR agonist.-   53. The method or use according to embodiment 52, wherein the RXR    agonist increases Foxp3 and/or α4β7 expression by at least 10%, at    least 20%, at least 30%, at least 40%, at least 50%, at least 60%,    at least 70%, at least 80%, at least 90%, at least 100%, at least    200%, at least 300%, at least 400%, or at least 500%, relative to    cells not exposed to the same RXR agonist.-   54. The method or use according to any one of embodiments 1-51,    wherein the RXR agonist increases Foxp3 and/or α4β7 expression in    naive CD4⁺ CD25⁻ FoxP3⁻ cells cultured under Treg cell    differentiation conditions.-   55. The method or use according to embodiment 54, wherein the RXR    agonist increases Foxp3 and/or α4β7 expression in naive CD4⁺ CD25⁻    FoxP3⁻ cells cultured under Treg cell differentiation by at least    10%, at least 20%, at least 30%, at least 40%, at least 50%, at    least 60%, at least 70%, at least 80%, at least 90%, at least 100%,    at least 200%, at least 300%, at least 400%, or at least 500%,    relative to naive CD4⁺ CD25⁻ FoxP3⁻ cells cultured under Treg cell    differentiation not exposed to the same RXR agonist.-   56. The method or use according to any one of embodiments 1-55,    wherein the RXR agonist has activity that inhibits Th17 cell    differentiation.-   57. The method or use according to embodiment 1-56, wherein the RXR    agonist inhibits Th17 cell differentiation by at least 10%, at least    20%, at least 30%, at least 40%, at least 50%, at least 60%, at    least 70%, at least 80%, at least 90%, at least 100%, at least 200%,    at least 300%, at least 400%, or at least 500%.-   58. The method or use according to any one of embodiments 1-57,    wherein the RXR agonist decreases IL-17A expression in cells exposed    to the RXR agonist.-   59. The method or use according to embodiment 58, wherein the RXR    agonist decreases IL-17A expression by at least 10%, at least 20%,    at least 30%, at least 40%, at least 50%, at least 60%, at least    70%, at least 80%, at least 90%, at least 100%, at least 200%, at    least 300%, at least 400%, or at least 500%, relative to cells not    exposed to the same RXR agonist.-   60. The method or use according to any one of embodiments 1-59,    wherein the RXR agonist decreases IL-17A expression in naive CD4⁺    CD25⁻ FoxP3⁻ cells cultured under Th17 cell differentiation    conditions.-   61. The method or use according to embodiment 60, wherein the RXR    agonist decreases IL-17A expression in naive CD4⁺ CD25⁻ FoxP3⁻ cells    cultured under Th17 cell differentiation by at least 10%, at least    20%, at least 30%, at least 40%, at least 50%, at least 60%, at    least 70%, at least 80%, at least 90%, at least 100%, at least 200%,    at least 300%, at least 400%, or at least 500%, relative to naive    CD4⁺ CD25⁻ FoxP3⁻ cells cultured under Treg cell differentiation not    exposed to the same RXR agonist.-   62. A method of promoting Treg cell differentiation in an    individual, the method comprising the step of administering to the    individual in need thereof a therapeutically effective amount of a    RXR agonist, wherein administration of the RXR agonist promotes Treg    cell differentiation.-   63. Use of a RXR agonist to promote Treg cell differentiation in an    individual, wherein administration of the RXR agonist to the    individual promotes Treg cell differentiation.-   64. The method according to embodiment 62 or use according to    embodiment 63, wherein administration of the RXR agonist to the    individual also inhibits Th17 cell differentiation.-   65. The method or use according to any one of embodiments 62-64,    wherein the RXR agonist is according to any one of embodiments 6-26    or 48-61.

EXAMPLES

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofrepresentative embodiments now contemplated. These examples should notbe construed to limit any of the embodiments described in the presentspecification, including those pertaining to the methods of treating anautoimmune disorder, inflammation associated with an autoimmunedisorder, or a transplant rejection using the RXR agonists disclosedherein, uses of a RXR agonists disclosed herein to manufacture amedicament and/or treat an autoimmune disorder, inflammation associatedwith an autoimmune disorder, or a transplant rejection, methods ofpromoting Treg cell differentiation in an individual, inhibiting Th17cell differentiation, or both, as well as uses of a RXR agonistsdisclosed herein to promote Treg cell differentiation in an individual,inhibit Th17 cell differentiation, or both.

Example 1 RXR Agonists Induce Treg Cell Differentiation

To determine whether a RXR agonist can induce Treg cell differentiation,the ability of an RXR agonist to promote Treg cell differentiation underTreg cell differentiation conditions was assessed by monitoring Foxp3and α4β7 expression. Naive CD4⁺ CD25⁻ FoxP3⁻ cells were purified from aFoxp3-GFP mouse using flow cytometry by sorting and isolating based upona GFP⁻ phenotype. These cells were then cultured under Treg celldifferentiation conditions by treating the cells with αCD3 and αCD28polyclonal antibodies in the presence of IL-2 and TGF-β. The culturedcells were incubated with RXR agonist 194204 (Formula XXIX) at 0.1 nM,1.0 nM and 10 nM and the expression of Foxp3 and α4β7 was analyzed. Theresults indicate that RXR agonist exerted significant impact on theexpression of Foxp3, inducing nearly 100% Foxp3⁺ T cells atconcentrations of 1 nM or higher. FIG. 1A. These results also indicatethat RXR agonist 194204 also induced expression of α4β7 (a gut homingreceptor). FIG. 1B. These results indicate that RXR agonists could beuseful in reducing a symptom of an autoimmune disorder or a transplantrejection.

Example 2 RXR Agonists Regulate T Cell Differentiation

To determine whether a RXR agonist can regulate T cell differentiation,the ability of an RXR agonist to promote Treg cell differentiation andinhibit Th17 cell differentiation under Th17 cell differentiationconditions was assessed by monitoring Foxp3 and IL-17A expression. NaiveCD4⁺ CD25⁻ FoxP3⁻ cells were purified from a Foxp3-GFP mouse using flowcytometry by sorting and isolating based upon a GFP-phenotype. Thesecells were then cultured under Th17 cell differentiation conditions inmedia with 0 nM, 1 nM, 10 nM, and 100 nM of RXR agonist 194204 (FormulaXXIX) and the expression of Foxp3 and IL-17A was analyzed. See, e.g.,Elias, et al., Retinoic Acid Inhibits Th17 Polarization and EnhancesFoxP3 Expression through a Stat-3/Stat-5 Independent Pathway, Blood111(3): 1-13-1020 (2008). The results indicated that as theconcentration of the RXR agonist increased, Foxp3 expression increased,indicating an increased presence of Treg cells. FIG. 2A. Additionally,the data demonstrate that as the concentration of the RXR agonistincreased, IL-17A expression decreased, indicating a decreased presenceof Th17 cells. FIG. 2B. These results indicate that RXR agonistsregulate T cell differentiation by promoting differentiation ofimmunosuppressive Treg cells and concurrently inhibiting differentiationof inflammatory Th17 cells from naïve T cells in vitro.

Example 3 RXR Agonists Regulate T Cell Differentiation Independent ofRAR Signaling

To determine whether a RXR agonist can mediate its effects via RAR/RXRreceptor heterodimers, via RXR receptor homodimers, or via some otherRXR containing complex, T cells were incubated with a RXR agonist in thepresence of a pan-RAR antagonist and the expression of Foxp3 wasassessed. Naive CD4⁺ CD25⁻ FoxP3⁻ cells were purified from a Foxp3-GFPmouse using flow cytometry by sorting and isolating based upon a GFP⁻phenotype. These cells were then cultured under Treg celldifferentiation conditions by treating the cells with αCD3 and αCD28polyclonal antibodies in the presence of IL-2 and TGF-β. The culturedcells were incubated with RXR agonist 194204 (Formula XXIX) at 1.0 nMtogether with 0 nM, 1 nM, or 10 nM of a pan-RAR antagonist 194310. Thecultured cells were then assayed for the expression of Foxp3. Theresults indicate that the inclusion of a pan-RAR antagonist onlypartially blocked the induction of Foxp3 expression observed with an RXRagonist alone. FIG. 3 . However, this partial inhibition of Fox3pexpression may actually be due to the blocking of the effects ofendogenous RA in the culture medium. As such, these results indicatethat the observed conversion of T cells into Treg cells appears to occurthrough the use of RXR receptor homodimers and/or some other RXRcontaining complex, and not through a RAR-mediated mechanism.

Example 4 T Cell Differentiation is Mediated Through RXR Signaling byRXR Agonists

To determine whether a RXR agonist can mediate its effects via an RXRαreceptor homodimers, RXRβ receptor homodimers, RXRγ receptor homodimers,or any combination thereof, or the corresponding RAR/RXR heterodimers,receptor-mediated transactivation assays were performed. Fortransactivation assays assessing RXR homodimer signaling, CV-1 cellswere transfected with 1) an expression construct including a full lengthRXRα, RXRβ, or RXRγ; and 2) a rCRBPII/RXRE-tk-Luc reporter constructthat included RXR homodimer-specific RXRE/DR1 responsive element linkedto a luciferase gene. For transactivation assays assessing RAR/RXRheterodimer signaling, CV-1 cells were transfected with 1) an expressionconstruct comprising a fusion protein including an estrogen receptor(ER) DNA binding domain linked to the ligand binding domain of RARα,RARβ, or RARγ and 2) a ERE-tk-Luc reporter construct that included anestrogen receptor responsive element linked to a luciferase gene. TheER-RAR fusion proteins provided an accurate readout of only thetransfected ER-RAR. After transfection, CV-1 cells were treated with RXRagonist 194204 (Formula XXIX) at increasing concentrations for 20 hoursbefore measuring luciferase activity. Luciferase activity is expressedas percent of maximal activity obtained using 1 μM RXR agonist 194204for RXRs and 1 μM all-trans-retinoic acid (ATRA) for RARs (Table 1).Data are mean values±SE from five independent experiments.

TABLE 1 RXR Agonist Potencies in Activating RXRs and RARs EC₅₀ (nM) EC₅₀(nM) Efficacy (% of 1 μM 194204) Efficacy (% of 1 μM ATRA) CompoundStructure RXRα RXRβ RXRγ RARα RARβ RARγ 194204

0.08 ± 0.01 100 0.47 ± 0.05 100 0.09 ± 0.01 100 >1,000 >1,000 >1,000

These results indicate that RXR agonist 194204 activated RXR receptorswith very high potency (EC₅₀<0.5 nM) for all three RXR subtypes (Table1). In contrast, EC₅₀ of the RXR agonist for RARs was >1,000 nM withminimal activity detected at ≥1 μM. This differencerepresents >2,000-fold selectivity for RXRs over RARs in functionaltransactivation assays. Additionally, these data demonstrate that RXRagonist 194204 was more than 1,000-fold more potent in activating RXRreceptors rather than RAR receptors. FIG. 4 . These results indicatethat Treg differentiation was mediated through a RXR signaling pathwayand not via a RAR signaling pathway. Also, using appropriate receptorand reporter constructs, RXR agonist 194204 was shown not totransactivate so called “permissive RXR heterodimers”, such as, e.g.,PPAR/RXR, FXR/RXR and LXR/RXR. In this regard, RXR agonist 194204 isdistinct from other RXR agonists.

Example 5 Binding Affinity of RXR Agonists

To determine the binding affinity for a RXR agonist, competitivedisplacement assays were performed. RXRα, RXRβ, RXRγ, RARα, RARβ, orRARγ were expressed in SF21 cells using a baclovirus expression systemand the resulting proteins were purified. To determine the bindingaffinity for a RXR agonist for an RXR, purified RXRα, RXRβ, and RXRγwere separately incubated with 10 nM [³H]-9CRA, and the binding affinityof the RXR agonist 194204 (Formula XXIX) was determined by competitivedisplacement of [³H]-9CRA from the receptor. To determine the bindingaffinity for a RXR agonist for an RAR, purified RARα, RARβ, and RARγwere incubated with 5 nM [³H]-ATRA, and the binding affinity of the RXRagonist 194204 (XXIX) was determined by competitive displacement of[³H]-ATRA from the receptor. Ki values are mean values of at least twoindependent experiments (Table 2). Standard errors (±) among independentexperiments are indicated.

As shown in Table 2, RXR agonist 194204 displayed high affinity forRXRα, RXRβ, and RXRγ with Ki values being 1.7, 16, and 43 nM,respectively. In contrast, the RXR agonist 194204 bound with very lowaffinity to each of the RARs (Ki values being>1,000 nM). These dataindicate that 194204 is highly selective for the RXRs relative to theRARs.

TABLE 2 RXR Agonist Binding Affinities RXR Binding Affinity RAR BindingAffinity Ki (nM) Ki (nM) Compound Structure RXRα RXRβ RXRγ RARα RARβRARγ 194204

1.7 ± 0.1 16 ± 1.0 43 ± 3.0 6344 ± 674 7552 ± 638 4742 ± 405

Example 6 RXR Agonists Attenuate EAE in B6 Mice

To determine whether a RXR agonist can attenuate multiple sclerosis,C57BL/6 (B6) mice were immunized (day 0) to induce EAE by subcutaneous(s.c.) injection at the base of their spine with 200 uL of adjuvantcontaining 125 ug myelin oligodendrocyte glycoprotein peptide (35-55)(MOG peptide; Peptides International, Louisville, Ky.) and 400 ugnon-viable M. tuberculosis H37 desiccate emulsified in a mixture ofincomplete Freund's adjuvant and phosphate buffered saline (PBS). Micewere also given 200 ng of pertussis toxin in PBS administered byinter-peritoneal (i.p.) injection on the same day as MOG emulsioninjection (day 0) and 2 days later (day 2). Starting on day 7 afterimmunization, mice were given the RXR agonist 194204 (50 ug) or vehiclecontrol i.p. every other day for the duration of the experiment (n=6-7mice/group). Statistics show the results of a Mann Whitney test(analyzed from start of treatment to the end of the experiment). Micewere scored using the following scale: 0—Mice have no disease, 1—Micehave distal limp tail or rear leg weakness (paresis), 1.5—Mice havedistal limp tail and rear leg weakness, 2—Mice have complete limp tailand rear leg weakness, 2.5—Mice have complete limp tail and weakness inboth rear legs, 3—Mice have complete limp tail and paralysis in bothrear legs, 3.5—Mice have complete limp tail, paralysis in both rearlegs, and forelimb weakness. Mice receiving a score of 3.5 wereimmediately euthanized.

FIG. 5 depicts scores of disease severity over time. The resultsindicate that administration of a RXR agonist significantly reduces thesymptoms of EAE in mice. Efficacy of the RXR agonist was observed afterthe first administration (day 7) and maintained throughout the course ofthe study (day 20).

Example 7 RXR Agonist-Treated Mice have Reduced Central Nervous SystemInfiltrating Cells

To determine whether a RXR agonist can reduce central nervous system(CNS) infiltrating cells, C57BL/6 (B6) mice were treated as described inExample 6. On day 20 after immunization, mice were sacrificed andperfused with phosphate buffered saline (PBS). Brain and spinal cordtissue was isolated, digested with DNase and Liberase DL (RocheDiagnostics, Indianapolis, Ind.) for 30 minutes, and homogenized through70 micron nylon mesh filters. Resulting cells were placed over a Percollgradient to remove myelin. The remaining cells (microglia and CNSinfiltrating cells) were counted, stained for molecules of interest, andrun on a flow cytometer. Based on the frequencies obtained by FACS ofthese cell populations, total cell numbers of CNS infiltratingleukocytes expressing CD45, including CD4⁺ T cells and CD11c⁺ CD11b⁺myeloid dendritic cells (DC), were calculated.

FIG. 6 compares the number of CD4⁺ cells or CD11c⁺ CD11b⁺ cells (myeloidDC) in mice treated with the RXR agonist 194204 verses the vehiclecontrol. There was a significant reduction in the infiltration of bothCD4⁺ cells and CD11c⁺ CD11b⁺ cells in animals treated with a RXR agonistas compared to the control. As disease is propagated in the CNS throughthe CD4⁺ cells infiltrating the CNS and becoming re-activated by CD11c⁺CD11b⁺ cells, this suggests that part of the mechanism of action in thismodel is to limit the presence of the cells in the CNS.

Example 8 RXR Agonists Attenuate EAE in SJL Mice

To determine whether a RXR agonist can attenuate multiple sclerosis, SJLmice were immunized to induce EAE by s.c. injection at the base of theirspine with 200 uL of adjuvant containing 200 ug proteolipid proteins(139-151) (PLP peptide; Peptides International, Louisville, Ky.) and 400ug of non-viable M. tuberculosis H37 desiccate emulsified in a mixtureof incomplete Freund's adjuvant and PBS. Mice were also given 150 ng ofpertussis toxin in PBS i.p. on the same day as PLP emulsion injectionand 2 days later. Starting day 7 after immunization, mice were given theRXR agonist 194204 (50 ug) or vehicle control i.p. every other day forthe duration of the experiment (n=6 mice/group). Mice were scored usingthe scale described in Example 6.

The results indicate that administration of a RXR agonist significantlyreduces the symptoms of EAE in mice. Table 3 shows the features of a RXRagonist 194204 treatment in SLJ mice. FIG. 7 depicts scores of diseaseseverity over time. Efficacy of the RXR agonist was observed after thesecond administration (day 8) and maintained throughout the course ofthe study (day 14).

TABLE 3 RXR agonist Treatment in SJL Mice Clinical Features Vehicle 4204Mean Maximum Score 3.2 ± 0.6 1.5 ± 1.4 Disease Incidence 6/6 4/6 Deathfrom Disease 4/6 0/6

In closing, it is to be understood that although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these disclosedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. Therefore, it should be understood that thedisclosed subject matter is in no way limited to a particularmethodology, protocol, and/or reagent, etc., described herein. As such,various modifications or changes to or alternative configurations of thedisclosed subject matter can be made in accordance with the teachingsherein without departing from the spirit of the present specification.Lastly, the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.Accordingly, the present invention is not limited to that precisely asshown and described.

Certain embodiments of the present invention are described herein,including the best mode known to the inventors for carrying out theinvention. Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor expects skilled artisans to employsuch variations as appropriate, and the inventors intend for the presentinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedembodiments in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentinvention are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical indication shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and values setting forth the broad scope ofthe invention are approximations, the numerical ranges and values setforth in the specific examples are reported as precisely as possible.Any numerical range or value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Recitation of numerical ranges ofvalues herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the present invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein is intended merely to betterilluminate the present invention and does not pose a limitation on thescope of the invention otherwise claimed. No language in the presentspecification should be construed as indicating any non-claimed elementessential to the practice of the invention.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the present invention so claimed areinherently or expressly described and enabled herein.

All patents, patent publications, and other publications referenced andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

What is claimed is:
 1. A method of treating an autoimmune skin disorder,wherein the autoimmune skin disease is not a psoriasis, the methodcomprising elevating Treg cell numbers and suppressing Th17 cell numbersin an individual having the autoimmune skin disorder by administering atherapeutically effective amount of a retinoid X receptor (RXR) agonisthaving the structure of formula XII:

or a pharmaceutically acceptable salt thereof; wherein R is H or loweralkyl of 1 to 6 carbons, wherein the therapeutically effective amount isabout 0.001 mg/kg/day to about 100 mg/kg/day; whereby the balancebetween Treg and Th17 cell development is modulated to restrainautoimmunity.
 2. The method according to claim 1, wherein the RXRagonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid, and has the structure of formula XXIX:

or a pharmaceutically acceptable salt thereof.
 3. The method accordingto claim 1, wherein the therapeutically effective amount is about 0.001mg/kg/day to about 0.2 mg/kg/day.
 4. The method according to claim 1,wherein the therapeutically effective amount is about 0.1 mg/kg/day toabout 3.0 mg/kg/day.
 5. The method according to claim 1, wherein R is H.6. The method according to claim 2, wherein the RXR agonist is a salt ofthe compound of formula XXIX.
 7. The method of claim 1, wherein theautoimmune skin disorder is an atopic eczema, a hidradenitissuppurativa, a scleroderma, or a discoid lupus erythematosus.
 8. Amethod of treating an autoimmune aspect of an autoimmune skin disorder,wherein the autoimmune skin disease is not a psoriasis, the methodcomprising concurrently promoting differentiation of Treg cells andinhibiting differentiation of Th17 cells using a single agent byadministering to an individual having the autoimmune skin disorder atherapeutically effective amount of a retinoid X receptor (RXR) agonisthaving the structure of formula XII:

or a pharmaceutically acceptable salt thereof; wherein R is H or loweralkyl of 1 to 6 carbons, wherein the therapeutically effective amount isabout 0.001 mg/kg/day to about 100 mg/kg/day; wherein the autoimmuneaspect comprises inflammation, an elevated Th17 to Treg cell ratio, ortissue destruction; whereby the autoimmune aspect of the autoimmune skindisorder is reduced.
 9. The method of claim 8, wherein the autoimmuneskin disorder is an atopic eczema, a hidradenitis suppurativa, adermatitis herpetiformis, a pemphigus vulgaris, a bullous pemphigoid, ascleroderma, a cutaneous lupus, or a discoid lupus erythematosus. 10.The method according to claim 7, wherein the RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid, and has the structure of formula XXIX:

or a pharmaceutically acceptable salt thereof.
 11. The method accordingto claim 8, wherein the therapeutically effective amount is about 0.001mg/kg/day to about 0.2 mg/kg/day.
 12. The method according to claim 8,wherein the therapeutically effective amount is about 0.1 mg/kg/day toabout 3.0 mg/kg/day.
 13. The method according to claim 8, wherein R isH.
 14. The method according to claim 10, wherein the RXR agonist is asalt of the compound of formula XXIX.
 15. The method according to claim1, wherein the RXR agonist is administered topically.
 16. The methodaccording to claim 8, wherein the RXR agonist is administered topically.17. The method of claim according to claim 1, wherein thetherapeutically effective amount is about 0.01 mg/kg/day to about 0.1mg/kg/day.
 18. The method of claim according to claim 8, wherein thetherapeutically effective amount is about 0.01 mg/kg/day to about 0.1mg/kg/day.
 19. The method according to claim 1, wherein elevating Tregcell numbers comprises promoting differentiation of Treg cells.
 20. Themethod according to claim 1, wherein suppressing Th17 cell numberscomprises inhibiting Th17 cell differentiation.
 21. The method accordingto claim 8, wherein the ratio of Th17 cells to Treg cells is reduced.